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2-aminobenzoyl-IEPDSSMEK-dnp + H2O
?
-
-
-
?
2-aminobenzoyl-IEPDSSMESK-dinitrophenyl + H2O
?
-
susbtrate is specific for human GrB
-
-
?
2-aminobenzoyl-IEPDSSMESK-dnp + H2O
?
-
-
-
?
2-aminobenzoyl-Val-Val-Ala-Asp-Ser-Ser-Met-Glu-Lys-dnp + H2O
?
-
-
-
?
2-aminobenzoyl-Val-Val-Ala-Glu-Ser-Ser-Met-Glu-Lys-dnp + H2O
?
-
-
-
?
2-aminobenzoyl-VVADSSMASK-dnp + H2O
?
-
-
-
?
2-aminobenzoyl-VVADSSMESK-dnp + H2O
?
-
-
-
?
2-aminobenzoyl-VVAESSMESK-dnp + H2O
?
-
-
-
?
28 kDa heat- and acid-stable phosphoprotein + H2O
?
-
-
-
-
?
28-kDa heat- and acid-stable phosphoprotein + H2O
?
-
-
-
-
?
3110082I17Rik protein + H2O
?
-
-
-
-
?
40 S ribosomal protein S25 + H2O
?
-
-
-
-
?
40 S ribosomal protein S4 + H2O
?
60 S ribosomal protein L10 + H2O
?
60 S ribosomal protein L3 + H2O
?
60 S ribosomal protein L5 + H2O
?
Abz-IEPDSSMESK-2,4-dinitrophenyl + H2O
?
-
-
-
-
?
Abz-IEPDSSMESK-DNP + H2O
?
-
-
-
-
?
Ac-IEPD-p-nitroanilide + H2O
Ac-IEPD + p-nitroaniline
Ace-Ile-Glu-Pro-Asp-p-nitroanilide + H2O
Ace-Ile-Glu-Pro-Asp + p-nitroaniline
-
-
-
-
?
acetyl-DEVD-7-amido-4-methylcoumarin + H2O
?
-
efficient cleavage by GzmB after K562 cells are exposed to sublytic perforin or streptolysin O. GzmH shows only baseline readings
-
-
?
acetyl-IAPD-7-amido-4-methylcoumarin + H2O
acetyl-IAPD + 7-amino-4-methylcoumarin
-
-
-
?
acetyl-IEFD-7-amido-4-methylcoumarin + H2O
acetyl-IEFD + 7-amino-4-methylcoumarin
-
-
-
?
acetyl-IEPD-4-nitroanilide + H2O
acetyl-IEPD + 4-nitroaniline
acetyl-IEPD-7-amido-4-methylcoumarin + H2O
acetyl-IEPD + 7-amino-4-methylcoumarin
-
-
-
?
acetyl-IEPD-p-nitroanilide + H2O
?
acetyl-IETD-7-amido-4-methylcoumarin + H2O
acetyl-IETD + 7-amino-4-methylcoumarin
acetyl-IETD-p-nitroanilide + H2O
?
-
-
-
-
?
acetyl-IKPD-7-amido-4-methylcoumarin + H2O
acetyl-IKPD + 7-amino-4-methylcoumarin
-
-
-
?
acetyl-Ile-Glu-Pro-Asp-4-nitroanilide + H2O
acetyl-Ile-Glu-Pro-Asp + 4-nitroaniline
acetyl-Ile-Glu-Pro-Asp-p-nitroanilide + H2O
?
-
-
-
-
?
acetyl-Ile-Glu-Thr-Asp-p-nitroanilide + H2O
?
-
-
-
-
?
acetyl-LEFD-7-amido-4-methylcoumarin + H2O
acetyl-LEFD + 7-amino-4-methylcoumarin
-
-
-
?
acetyl-LEPD-7-amido-4-methylcoumarin + H2O
acetyl-LEPD + 7-amino-4-methylcoumarin
-
-
-
?
acetyl-VDVADAFC + H2O
acetyl-VDVAD + Ala-Phe-Lys
-
GzmH
-
-
?
acetyl-VEID-4-nitroanilide + H2O
acetyl-VEID + 4-nitroaniline
acetyl-YVAD-4-nitroanilide + H2O
acetyl-YVAD + 4-nitroaniline
-
an asp-ase substrate
-
-
?
acetylcholine receptor
?
-
granzyme B efficiently and specifically cleaves alpha and epsilon subunits of acetylcholine receptor, especially the epsilon subunit
-
-
?
acetylcholine receptor + H2O
?
-
extracellular GrB substrate. Implication: cleavage results in a reduction of the receptor in neuromuscular junctions and yields an autoantigenic fragment
-
-
?
acetylcholine receptor epsilon subunit + H2O
?
-
-
-
-
?
acidic leucine-rich nuclear phosphoprotein 32 family member B + H2O
?
acidic leucine-rich nuclear phosphoprotein 32 family member E + H2O
?
actin-like protein 6A + H2O
?
adenovirus 100K assembly protein + H2O
?
-
gzmB and gzmH
-
-
?
adenovirus DNA-binding protein + H2O
?
-
gzmB and gzmH. Direct cleavage of DNA-binding protein by gzmH is a critical component of the cytotoxic antiviral response against adenovirus, which slows down DNA viral replication. Cleaved by gzmH at multiple sites, most efficient cleavage at Met118, when this site is mutated, gzmH instead cleaves at Phe121
-
-
?
aggrecan + H2O
?
-
extracellular GrB substrate. Implication: Disruption of structural integrity in cartilage
-
-
?
aggrecan proteoglycan + H2O
?
-
-
-
-
?
AHNAK + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: calcium signalling, associated disease: systemic lupus erythematosus
-
-
?
alanyl tRNA synthetase + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: translation, associated disease: myositis
-
-
?
alpha-fodrin + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: cytoskeletal protein, associated disease: Sjörgen's syndrome
-
-
?
alpha-tubulin
?
-
-
-
-
?
alpha-tubulin + H2O
truncated alpha-tubulin
-
alpha-tubulin derived from HeLa S100 extracts or Jurkat S100 extracts is cleaved by grB in a caspase-independent manner. Cleavage occurs at D438. Polymerized and soluble alpha-tubulin can be cleaved
-
-
?
anamorsin + H2O
?
-
-
-
-
?
AQGVISADASNLDDFY + H2O
AQGVISAD + ASNLDDFY
-
-
-
-
?
AQGVISASASNLDDFY + H2O
AQGVISAS + ASNLDDFY
-
-
-
-
?
ARF GTPase-activating protein GIT2 + H2O
?
-
-
-
-
?
ATSY-7-amido-4-methylcoumarin + H2O
ATSY + 7-amino-4-methylcoumarin
-
GzmH
-
-
?
autoantigen + H2O
?
-
-
-
-
?
Bcl-2-associated athano gene-1 + H2O
?
-
GrB proteolysis is independent of caspase activity
-
-
?
BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 + H2O
?
-
generated with similar efficiency by mouse and human recombinant granzyme B
-
-
?
BCL2/adenovirus E1B 19-kDa protein-interacting protein 2 + H2O
?
-
generated with similar efficiency by mouse and human recombinant granzyme B
-
-
?
beta-actin + H2O
?
-
GrB cleavage fragments of beta-actin are detected in medullary carcinoma of the breast tumor lysates, suggesting that CTL-mediated death of medullary carcinoma of the breast tumor cells and actin redistribution may have a function in the generation of autoimmunity to beta-actin
-
-
?
BID + H2O
truncated BID + ?
Boc-Ala-Ala-Asp-SBzl + H2O
?
cartilage proteoglycans + H2O
?
-
extracellular GrB substrate. Implication: Disruption of structural integrity in cartilage
-
-
?
caspase-3 + H2O
procaspase-3 + ?
-
gzmB
-
-
?
caspase-8 + H2O
?
-
cleaves human caspase-8 but fails to cleave the mouse counterpart of caspase-8. Mouse caspase-8 is processed only upon addition of cytochrome c and dATP to J774 extracts to activate the apoptosome pathway to caspase activation
-
-
?
cell division cycle 5-like protein + H2O
?
cell division cycle 5-related protein + H2O
?
centromere protein B + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: mitosis, associated disease: Scleroderma
-
-
?
centromere protein C + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: mitosis, associated disease: Scleroderma
-
-
?
chromodomain helicase DNA binding 4 + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: gene expression, associated disease: myositis
-
-
?
chromodomain-helicase-DNA-binding protein 7 + H2O
?
ClpA unfoldase + H2O
?
Escherichia coli ClpA
-
-
?
ClpP protease + H2O
?
Escherichia coli ClpP
-
-
?
ClpS adaptor + H2O
?
Escherichia coli ClpS
-
-
?
dedicator of cytokinesis protein 2 + H2O
?
-
-
-
-
?
DNA binding protein + H2O
?
-
granzyme B and granzyme H (cleavage at Met118 and Phe121)
-
-
?
DNA-PK catalytic subunit + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: DNA repair, associated disease: myositis
-
-
?
double strand break repair protein MRE11A + H2O
?
-
-
-
-
?
E3 SUMO-protein ligase RanBP2 + H2O
?
embryo heart cDNA + H2O
?
-
-
-
-
?
enhancer of mRNA-decapping protein 3 + H2O
?
eukaryotic translation initiation factor 2 subunit 2 + H2O
?
-
-
-
-
?
exportin-5 + H2O
?
-
-
-
-
?
FGFR1 + H2O
?
-
extracellular GrB substrate. Implication: cleavage activates pro-cell death functions as well as inactivates pro-growth signals
-
-
?
fibrillin-1 + H2O
?
-
-
-
?
fibroblast growth factor receptor-1 + H2O
?
-
-
-
-
?
glutamate receptor subunit 3 + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: Glutamate receptor, associated disease: Rasmussen's encephalitis
-
-
?
Glutamyl 2-naphthylamide + H2O
?
GTP-binding protein 1 + H2O
?
-
-
-
-
?
hepatitis antigen lamin B + H2O
?
-
cleavage of autoimmune hepatitis antigen lamin B by GrA and B causes disruption of the nuclear lamina, by uncoupling lamin B from its nuclear localisation signal
-
-
?
heterogeneous nuclear ribonucleoprotein H' + H2O
?
-
-
-
-
?
histidyl tRNA synthetase + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: translation, associated disease: myositis
-
-
?
Hsc70/Hsp70-interacting protein + H2O
?
-
Hsc70/Hsp70-interacting protein is cleaved at both GrB cleavage sites (at sequences IEPD92-TD and INPD180-SA) during NK-mediated cell death in a caspase-independent manner. Hsc70/Hsp70-interacting protein is a substrate unique to GrB
-
-
?
Hsp70/Hsp90-organizing protein + H2O
?
Hsp90 + H2O
?
-
is proteolyzed at multiple sites by GrB. Cleavage at sequences IDED693-EV and INPD631-PI in Hsp90beta. Cleavage at sequences IDED701-DP, INPD639-HS and VRTD175-TG in Hsp90alpha
-
-
?
human endogenous retrovirus K-10 gag + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: endogenous retrovirus, associated disease: systemic lupus erythematosus
-
-
?
ICAD + H2O
?
-
cleaves human ICAD but fails to cleave the mouse counterpart
-
-
?
IEPD-p-nitroanilide + H2O
?
-
-
-
-
?
inhibitor of caspase-activated DNase + H2O
caspase-activated DNase
-
cleaved in a dose-dependent fashion
-
-
?
interleukin IL-1alpha + H2O
?
-
cleavage after the motif IAND103, no substrate for caspases -1, -3, -4, -5, and -7
granzyme B-mediated processing of IL-1alpha potently enhances the biological activity
-
?
interleukin proIL-18 + H2O
interleukin IL-18 + ?
-
-
cleavage at residues D35-Y36 of proIL-18, identical to cleavage site of caspase-1
-
?
intersectin-1 + H2O
?
-
-
-
-
?
Ki-67 + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: proliferation, associated disease: myositis
-
-
?
kinesin family member 21A + H2O
?
Ku-70 + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: DNA repair, associated disease: myositis
-
-
?
L4-100k assembly protein + H2O
?
-
granzyme H
-
-
?
La protein + H2O
?
-
La is cleaved by gzmB and gzmH. La is a direct target of gzmH during cytotoxic-mediated cell death. Cleavage of La by gzmH occurs at Phe-364 (P(1) site) and generates a COOH-terminal truncated form of La that loses nuclear localization and decreases hepatitis C virus-internal ribosome entry site-mediated translational activity
-
-
?
La/SSB + H2O
?
-
the SS nuclear autoantigen La/SSB is a substrate for GrB
-
-
?
lamin B + H2O
?
-
-
-
-
?
Laminin + H2O
?
-
extracellular GrB substrate. Implication: cell adhesion, anoikis
-
-
?
LEADKGKLEYD + H2O
LEAD + KGKLEYD
LEED-p-nitroanilide + H2O
?
-
-
-
-
?
MFLJ00057 protein + H2O
?
-
-
-
-
?
microtubule-associated protein 4 + H2O
?
N-acetyl-L-Ile-L-Glu-L-Pro-L-Asp-4-nitroanilide + H2O
?
-
-
-
-
?
Nalpha-tert-Butyloxycarbonyl-Ala-Ala-Asn thiobenzyl ester + H2O
?
-
-
-
-
?
Nalpha-tert-Butyloxycarbonyl-Ala-Ala-Met thiobenzyl ester + H2O
?
Nalpha-tert-Butyloxycarbonyl-L-Ala-Ala-Ser thiobenzyl ester + H2O
?
-
-
-
-
?
Nalpha-tert-Butyloxycarbonyl-L-Ala-L-Ala-L-Asp thiobenzyl ester + H2O
?
negative elongation factor E + H2O
?
-
-
-
-
?
neuronal glutamate receptor + H2O
?
-
extracellular GrB substrate. Implication: GrB cleaves the non-glycosylated form of the receptor into an autoantigenic fragment
-
-
?
nipped-B-like protein + H2O
?
nuclear mitotic apparatus protein 1 + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: mitosis, associated disease: Sjörgen's syndrome
-
-
?
nuclease-sensitive element-binding protein 1 + H2O
?
-
-
-
-
?
nucleolus organizing region 90 kDa (NOR-90/UBF) + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: transcription factor, associated disease: Scleroderma
-
-
?
nucleophosmin (B23) + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: rRNA processing, associated disease: Scleroderma
-
-
?
nucleophosmin + H2O
?
-
efficiently cleaves nucleophosmin of human origin, does not cleave nucleophosmin within J774 cell free extracts
-
-
?
nucleosome assembly protein 1-like + H2O
?
-
-
-
-
?
p35 + H2O
?
-
GrB-induces phosphorylation of p53
-
-
?
PARP-PKcs + H2O
?
-
-
-
?
PEG-P + H2O
?
-
virtually all soluble PEG-P is cleaved in 3 min, suggesting PEG-P is a sensitive indicator of granzyme B activity. The granzyme can not access PEG-P when encapsulated in 1,2-dioleoyl-sn-glycero-3-phosphocholine large unilamellar vesicles
-
-
?
peptidyl-prolyl cis-trans isomerase G + H2O
?
peptidyl-prolyl cis-trans isomerase-like 4 + H2O
?
-
-
-
-
?
peptidylarginine deiminase 4 + H2O
PAD4 peptides
pericentriolar material 1 protein + H2O
?
-
-
-
-
?
plasmin + H2O
?
-
extracellular GrB substrate. Implication: as plasmin is pro-angiogenic, cleavage results in the reduction of angiogenesis
-
-
?
plasminogen + H2O
?
-
extracellular GrB substrate. Implication: cleavage yields angiostatin, which is anti-angiogenic. Implications in angiogenesis
-
-
?
PMScl/EXOSC10 + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: mRNA degradation, associated disease: myositis/Scleroderma
-
-
?
poly(ADP)ribose polymerase 1 (PARP1) + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: ribosylation, associated disease: systemic lupus erythematosus
-
-
?
poly(ADP-ribose) polymerase + H2O
?
-
-
-
-
?
poly(ADP-ribose)polymerase + H2O
?
-
-
-
-
?
poly-a binding protein + H2O
?
-
-
-
-
?
polypyrimidine tract-binding protein + H2O
?
postmeiotic segregation 1 + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: DNA mismatch repair, associated disease: myositis
-
-
?
postmeiotic segregation 2 + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: DNA mismatch repair, associated disease: myositis
-
-
?
pro-caspase 3 + H2O
?
-
-
-
-
?
pro-caspase 3 + H2O
p17 + ?
-
-
-
-
?
pro-caspase-3 + H2O
caspase-3 + ?
pro-caspase-7 + H2O
caspase-7 + ?
-
-
-
-
?
pro-CPP32 + H2O
?
-
processes the caspase into its enzymatically active form
-
?
pro-mCASP-3 + H2O
caspase-3 + ?
pro-mCASP-7 + H2O
caspase-7 + ?
probable rRNA-processing protein EBP2 + H2O
?
-
-
-
-
?
procaspase-8 + H2O
caspase-8 + ?
-
-
-
-
?
Protease CMH-1 + H2O
?
-
a close homologue of CPP32, granzyme B specifically cleaves at Asp198-Ser199 between the p20 and p12 and activates the cysteine protease
-
-
?
protein phosphatase 1G + H2O
?
-
-
-
-
?
PTSY-7-amido-4-methylcoumarin + H2O
PTSY + 7-amino-4-methylcoumarin
-
GzmH
-
-
?
pyruvate dehydrogenase complex E2 (PDC-E2) + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: acetyl CoA synthesis, associated disease: primary biliary cirrhosis
-
-
?
RNA polymerase I + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: transcription, associated disease: Scleroderma
-
-
?
RNA polymerase II + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: transcription, associated disease: Scleroderma
-
-
?
RNA-binding protein 28 + H2O
?
scaffold attachment factor B + H2O
?
-
-
-
-
?
serine/arginine-repetitive matrix protein 1 + H2O
?
-
-
-
-
?
serine/arginine-repetitive matrix protein 2 + H2O
?
serine/threonine protein kinase N1 + H2O
?
serum deprivation-response protein + H2O
?
-
-
-
-
?
signal recognition particle 72 kDa + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: translation, associated disease: myositis, systemic lupus erythematosus
-
-
?
smooth muscle cell matrix + H2O
?
-
extracellular GrB substrate. Implication: cell adhesion, anoikis
-
-
?
splicing factor 3B subunit 1 + H2O
?
squamous cell carcinoma antigen recognized by T-cells 3 + H2O
?
succinyl-Phe-Leu-Phe-p-nitroanilide + H2O
?
-
-
-
-
?
succinyl-Phe-Leu-Phe-SBzl + H2O
?
-
GzmH
-
-
?
T-complex protein 1 subunit alpha + H2O
?
testis-specific Y-encoded-like protein 2 + H2O
?
-
-
-
-
?
topoisomerase 1 + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: transcription, associated disease: Scleroderma
-
-
?
topoisomerase-1 + H2O
?
-
-
-
?
transaldolase + H2O
?
-
specifically cleaved by human GrB. The recognition site is a VVAD motif at aa residue 27
the major C-terminal GrB cleavage product of transaldolase, residues 28-337, has no enzymatic activity but retains the antigenicity of full-length transaldolase, effectively stimulating the proliferation and cytotoxic lymphocyte activity of peripheral blood mononuclear cells and of CD8+ T cell lines from patients with multiple sclerosis. Sera of multiple sclerosis patients exhibit similar binding affinity to wild-type and GrB-cleaved transaldolase
-
?
transcription elongation factor A protein 1 + H2O
?
-
-
-
-
?
U1 small nuclear ribonucleoprotein 70 kDa + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: RNA processing, associated disease: systemic lupus erythematosus, Scleroderma, myositis
-
-
?
U3 small nucleolar RNA-associated protein 18 homolog + H2O
?
-
-
-
-
?
U4/U6.U5 tri-snRNP-associated protein 1 + H2O
?
-
-
-
-
?
ubiquitin C-terminal hydrolase 10 + H2O
?
-
-
-
-
?
ubiquitin fusion degradation 2 + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: ubiquitination, associated disease: Scleroderma
-
-
?
ubiquitin thioesterase OTUB1 + H2O
?
uncharacterized protein KIAA0859 + H2O
?
-
-
-
-
?
VEID-p-nitroanilide + H2O
?
-
-
-
-
?
VGPDFGR + H2O
VGPD + FGR
-
-
-
-
?
von Willebrand factor + H2O
?
additional information
?
-
40 S ribosomal protein S4 + H2O
?
-
X isoform
-
-
?
40 S ribosomal protein S4 + H2O
?
-
X isoform
-
-
?
60 S ribosomal protein L10 + H2O
?
-
-
-
-
?
60 S ribosomal protein L10 + H2O
?
-
-
-
-
?
60 S ribosomal protein L3 + H2O
?
-
-
-
-
?
60 S ribosomal protein L3 + H2O
?
-
-
-
-
?
60 S ribosomal protein L5 + H2O
?
-
-
-
-
?
60 S ribosomal protein L5 + H2O
?
-
-
-
-
?
Ac-IEPD-p-nitroanilide + H2O
Ac-IEPD + p-nitroaniline
-
-
-
?
Ac-IEPD-p-nitroanilide + H2O
Ac-IEPD + p-nitroaniline
-
-
-
-
?
acetyl-IEPD-4-nitroanilide + H2O
acetyl-IEPD + 4-nitroaniline
an asp-ase substrate, high activity
-
-
?
acetyl-IEPD-4-nitroanilide + H2O
acetyl-IEPD + 4-nitroaniline
-
an asp-ase substrate
-
-
?
acetyl-IEPD-p-nitroanilide + H2O
?
-
-
-
?
acetyl-IEPD-p-nitroanilide + H2O
?
-
-
-
-
?
acetyl-IETD-7-amido-4-methylcoumarin + H2O
acetyl-IETD + 7-amino-4-methylcoumarin
-
-
-
-
?
acetyl-IETD-7-amido-4-methylcoumarin + H2O
acetyl-IETD + 7-amino-4-methylcoumarin
-
-
-
-
?
acetyl-IETD-7-amido-4-methylcoumarin + H2O
acetyl-IETD + 7-amino-4-methylcoumarin
-
-
-
?
acetyl-Ile-Glu-Pro-Asp-4-nitroanilide + H2O
acetyl-Ile-Glu-Pro-Asp + 4-nitroaniline
-
-
-
?
acetyl-Ile-Glu-Pro-Asp-4-nitroanilide + H2O
acetyl-Ile-Glu-Pro-Asp + 4-nitroaniline
-
-
-
?
acetyl-VEID-4-nitroanilide + H2O
acetyl-VEID + 4-nitroaniline
an asp-ase substrate, low activity
-
-
?
acetyl-VEID-4-nitroanilide + H2O
acetyl-VEID + 4-nitroaniline
-
an asp-ase substrate
-
-
?
acidic leucine-rich nuclear phosphoprotein 32 family member B + H2O
?
-
-
-
-
?
acidic leucine-rich nuclear phosphoprotein 32 family member B + H2O
?
-
-
-
-
?
acidic leucine-rich nuclear phosphoprotein 32 family member E + H2O
?
-
-
-
-
?
acidic leucine-rich nuclear phosphoprotein 32 family member E + H2O
?
-
-
-
-
?
actin-like protein 6A + H2O
?
-
-
-
-
?
actin-like protein 6A + H2O
?
-
-
-
-
?
beta-glycan + H2O
?
-
-
-
?
beta-glycan + H2O
?
100 kDa protein, cleavage by the enzyme into fragments of about 60 kDa and 40 kDa
-
-
?
BID + H2O
truncated BID + ?
-
-
-
-
?
BID + H2O
truncated BID + ?
-
efficiently cleaves both human or mouse BID
-
-
?
BID + H2O
truncated BID + ?
-
both human and mouse BID are cleaved efficiently
-
-
?
BID + H2O
truncated BID + ?
-
cleaved in a dose-dependent fashion
-
-
?
BID + H2O
truncated BID + ?
-
efficient cleavage of mouse and human Bid by human granzyme B
-
-
?
BID + H2O
truncated BID + ?
-
-
-
-
?
biglycan + H2O
?
-
-
-
?
biglycan + H2O
?
40 kDa protein, cleavage by the enzyme into fragments of about 30 kDa and 20 kDa
-
-
?
Boc-Ala-Ala-Asp-SBzl + H2O
?
-
-
-
?
Boc-Ala-Ala-Asp-SBzl + H2O
?
-
-
-
?
Boc-Ala-Ala-Asp-SBzl + H2O
?
-
-
-
?
Boc-Ala-Ala-Asp-SBzl + H2O
?
-
-
-
?
Boc-Ala-Ala-Asp-SBzl + H2O
?
-
-
-
?
Boc-Ala-Ala-Asp-SBzl + H2O
?
-
-
-
?
cell division cycle 5-like protein + H2O
?
-
-
-
-
?
cell division cycle 5-like protein + H2O
?
-
-
-
-
?
cell division cycle 5-related protein + H2O
?
-
-
-
-
?
cell division cycle 5-related protein + H2O
?
-
-
-
-
?
chromodomain-helicase-DNA-binding protein 7 + H2O
?
-
-
-
-
?
chromodomain-helicase-DNA-binding protein 7 + H2O
?
-
-
-
-
?
ClpX unfoldase + H2O
?
Escherichia coli ClpX
-
-
?
ClpX unfoldase + H2O
?
Escherichia coli N-terminal GST-tagged 37kDa ClpX. Human GzmB is predicted to cut ClpX after Asp144, in the AAA domain and interfere with its unfolding activity
-
-
?
decorin + H2O
?
-
-
-
?
decorin + H2O
?
65 kDa protein, cleavage by the enzyme into fragments of about 50 kDa and 30 kDa
-
-
?
DNA-PKcs + H2O
?
-
-
-
?
DNA-PKcs + H2O
?
-
directly and efficiently cleaved in vitro and in vivo, abolishes kinase activity
-
?
DNA-PKcs + H2O
?
-
directly and efficiently cleaved in vitro and in vivo, abolishes kinase activity
-
?
E3 SUMO-protein ligase RanBP2 + H2O
?
-
-
-
-
?
E3 SUMO-protein ligase RanBP2 + H2O
?
-
-
-
-
?
enhancer of mRNA-decapping protein 3 + H2O
?
-
-
-
-
?
enhancer of mRNA-decapping protein 3 + H2O
?
-
-
-
-
?
fibrillarin + H2O
?
-
-
-
?
fibrillarin + H2O
?
-
autoantigen cleaved by granzyme B, function of substrate: rRNA processing, associated disease: Scleroderma
-
-
?
Fibrinogen + H2O
?
-
granzyme B is unable to cleave soluble fibrinogen, granzyme B cleaves the matrix form at several sites
-
-
?
Fibrinogen + H2O
?
-
extracellular GrB substrate. Implication: matrix form of fibrinogen is cleaved. The uncleaved protein is responsible for platelet adhesion and thrombus growth. Cleavage results in anti-thrombosis implications
-
-
?
Fibronectin + H2O
?
-
-
-
-
?
Fibronectin + H2O
?
-
extracellular GrB substrate. Implication: cell adhesion, migration, and anoikis
-
-
?
gamma-taxilin + H2O
?
-
-
-
-
?
gamma-taxilin + H2O
?
-
-
-
-
?
Glutamyl 2-naphthylamide + H2O
?
-
-
-
-
?
Glutamyl 2-naphthylamide + H2O
?
-
-
-
-
?
Hsp70/Hsp90-organizing protein + H2O
?
-
-
-
-
?
Hsp70/Hsp90-organizing protein + H2O
?
-
directly cleaved at Asp186 in vitro and in cells undergoing GzmB-induced death. Processing by GzmB is caspase-independent. Cleavage by GzmB destroys known functions of Hsp70/Hsp90-organizing protein in Hsp binding and hormone receptor assembly
-
-
?
kinesin family member 21A + H2O
?
-
-
-
-
?
kinesin family member 21A + H2O
?
-
-
-
-
?
LEADKGKLEYD + H2O
LEAD + KGKLEYD
-
is a far better substrate for mouse granzyme B as compared with human granzyme B
-
-
?
LEADKGKLEYD + H2O
LEAD + KGKLEYD
-
is a far better substrate for mouse granzyme B as compared with human granzyme B
-
-
?
microtubule-associated protein 4 + H2O
?
-
-
-
-
?
microtubule-associated protein 4 + H2O
?
-
-
-
-
?
Nalpha-tert-Butyloxycarbonyl-Ala-Ala-Met thiobenzyl ester + H2O
?
-
-
-
-
?
Nalpha-tert-Butyloxycarbonyl-Ala-Ala-Met thiobenzyl ester + H2O
?
-
-
-
-
?
Nalpha-tert-Butyloxycarbonyl-L-Ala-L-Ala-L-Asp thiobenzyl ester + H2O
?
-
-
-
-
?
Nalpha-tert-Butyloxycarbonyl-L-Ala-L-Ala-L-Asp thiobenzyl ester + H2O
?
-
-
-
-
?
nipped-B-like protein + H2O
?
-
-
-
-
?
nipped-B-like protein + H2O
?
-
-
-
-
?
Notch1 + H2O
?
-
-
-
-
?
Notch1 + H2O
?
-
extracellular GrB substrate. Implication: cleavage results in cell signaling affecting tumor survival and antiviral activities
-
-
?
Notch1 + H2O
?
-
transmembrane receptor, Notch1 is a direct and caspase-independent substrate. GrB cleaves the intracellular Notch1 domain at least twice, at residues D1860 and D1961. GrB cleavage of Notch1 can occur in all subcellular compartments, during maturation of the receptor, at the membrane, and in the nucleus. GrB also displays perforin-independent functions by cleaving the extracellular domain of Notch1
cleavage of Notch1 by GrB results in a loss of transcriptional activity, independent of Notch1 activation. GrB disables Notch1 function, probably resulting in anti-cellular proliferation and cell death signals
-
?
nucleolin + H2O
?
-
-
-
-
?
nucleolin + H2O
?
-
-
-
-
?
NuMA + H2O
?
-
-
-
?
NuMA + H2O
?
-
directly and efficiently cleaved in vitro and in vivo
-
?
pallidin + H2O
?
-
-
-
-
?
pallidin + H2O
?
-
-
-
-
?
peptidyl-prolyl cis-trans isomerase G + H2O
?
-
-
-
-
?
peptidyl-prolyl cis-trans isomerase G + H2O
?
-
-
-
-
?
peptidylarginine deiminase 4 + H2O
PAD4 peptides
-
GrB cleaves PAD4 exclusively at D388
-
-
?
peptidylarginine deiminase 4 + H2O
PAD4 peptides
-
PAD4, is cleaved by GrB at a single site, aspartic acid 388 (D388). Dynamic changes occur in the PAD4 structure induced by GrB cleavage. Recombinant N-terminal 6xHis tagged PAD4 (NP_036519) is expressed and purified from Escherichia coli BL21(DE3)pLysS competent cells
-
-
?
polypyrimidine tract-binding protein + H2O
?
-
2times more efficiently cleaved by mouse versus human recombinant granzyme B
-
-
?
polypyrimidine tract-binding protein + H2O
?
-
2times more efficiently cleaved by mouse versus human recombinant granzyme B
-
-
?
pro-caspase-10 + H2O
?
-
-
-
?
pro-caspase-10 + H2O
?
-
-
-
?
pro-caspase-3 + H2O
?
-
-
-
-
?
pro-caspase-3 + H2O
?
-
activates caspase-3, whether of human or murine origin, with a similar efficiency
-
-
?
pro-caspase-3 + H2O
?
-
granzyme B
-
-
?
pro-caspase-3 + H2O
?
-
activates caspase-3, whether of human or murine origin, with a similar efficiency
-
-
?
pro-caspase-3 + H2O
caspase-3 + ?
-
-
-
-
?
pro-caspase-3 + H2O
caspase-3 + ?
-
cleaves human pro-caspase-3 generating a 21-kDa and a 17-kDa fragment (autocatalytic removal of the caspase-3 prodomain)
-
-
?
pro-caspase-3 + H2O
caspase-3 + ?
-
-
-
-
?
pro-caspase-3 + H2O
caspase-3 + ?
-
cleaves human pro-caspase-3 but only generates a 21-kDa fragment, no autocatalytic removal of the caspase-3 prodomain. Efficiently cleaves and activates mouse procaspase-3, producing predominantly the 17-kDa fragment
-
-
?
pro-caspase-7 + H2O
?
-
activates caspase-7, whether of human or murine origin, with a similar efficiency
-
-
?
pro-caspase-7 + H2O
?
-
activates caspase-7, whether of human or murine origin, with a similar efficiency
-
-
?
pro-mCASP-3 + H2O
caspase-3 + ?
-
-
-
?
pro-mCASP-3 + H2O
caspase-3 + ?
-
-
-
?
pro-mCASP-3 + H2O
caspase-3 + ?
-
activational cleavage of the caspase proform
-
?
pro-mCASP-7 + H2O
caspase-7 + ?
-
-
-
?
pro-mCASP-7 + H2O
caspase-7 + ?
-
-
-
?
pro-mCASP-7 + H2O
caspase-7 + ?
-
activational cleavage of the caspase proform
-
?
Protease CPP32 + H2O
?
-
CPP32 is the precursor of the protease responsible for cleavage of poly(ADPribose)polymerase
-
-
?
Protease CPP32 + H2O
?
-
granzyme B activates CPP32, which is now able to bind inhibitors and cleave the substrate poly(ADPribose)polymerase whose proteolysis is a marker of apoptosis initiated by several other stimuli
-
-
?
RNA-binding protein 28 + H2O
?
-
-
-
-
?
RNA-binding protein 28 + H2O
?
-
-
-
-
?
serine/arginine-repetitive matrix protein 2 + H2O
?
-
-
-
-
?
serine/arginine-repetitive matrix protein 2 + H2O
?
-
-
-
-
?
serine/threonine protein kinase N1 + H2O
?
-
-
-
-
?
serine/threonine protein kinase N1 + H2O
?
-
-
-
-
?
splicing factor 3B subunit 1 + H2O
?
-
-
-
-
?
splicing factor 3B subunit 1 + H2O
?
-
-
-
-
?
squamous cell carcinoma antigen recognized by T-cells 3 + H2O
?
-
-
-
-
?
squamous cell carcinoma antigen recognized by T-cells 3 + H2O
?
-
-
-
-
?
T-complex protein 1 subunit alpha + H2O
?
-
-
-
-
?
T-complex protein 1 subunit alpha + H2O
?
-
-
-
-
?
ubiquitin thioesterase OTUB1 + H2O
?
-
-
-
-
?
ubiquitin thioesterase OTUB1 + H2O
?
-
-
-
-
?
Vitronectin + H2O
?
-
-
-
-
?
Vitronectin + H2O
?
-
Grb expressed in human bladder cancer cell lines 1512 and RT112 cleave vitronectin
-
-
?
Vitronectin + H2O
?
-
extracellular GrB substrate. Implication: GrB cleavage site in integrin-binding domain, implications in cell adhesion, migration, and anoikis
-
-
?
von Willebrand factor + H2O
?
-
granzyme B delays ristocetin-induced platelet aggregation and inhibits platelet adhesion and spreading on immobilized von Willebrand factor under static conditions. In vitro, granzyme B cannot cleave the von Willebrand factor conformer in solution, but cleavage is induced when von Willebrand factor is artificially unfolded or presented as a matrix. Granzyme B cleaves von Willebrand factor with comparable efficiency to proteinase ADAMTS-13 and rapidly processes ultra-large von Willebrand factor multimers released from activated endothelial cells under physiological shear. Granzyme B cleaves the A1 and A3 domains of von Willebrand factor
-
-
?
von Willebrand factor + H2O
?
-
extracellular GrB substrate. Implication: GrB cleavage site in the domain of platelet interaction, prevention/delay of thrombosis
-
-
?
additional information
?
-
no activity with succinyl-Gly-Gly-Phe-4-nitroanilide
-
-
?
additional information
?
-
-
no activity with succinyl-Gly-Gly-Phe-4-nitroanilide
-
-
?
additional information
?
-
no activity with succinyl-Gly-Gly-Phe-4-nitroanilide
-
-
?
additional information
?
-
-
preference for substrates with Glu or Asp as the residue amino-terminal to the scissile bond, little or no activity with oligopeptide substrates for trypsin-like, chymotrypsin-like, and elastase-like proteases
-
-
?
additional information
?
-
-
preference for substrates with Glu or Asp as the residue amino-terminal to the scissile bond, little or no activity with oligopeptide substrates for trypsin-like, chymotrypsin-like, and elastase-like proteases
-
-
?
additional information
?
-
-
induces DNA degradation and apoptosis of cells
-
?
additional information
?
-
-
requirement for aspartic acid in the substrate P1 position
-
?
additional information
?
-
-
requirement for aspartic acid in the substrate P1 position
-
?
additional information
?
-
-
plays an essential role in cytotoxic T-lymphocyte-mediated cell killing
-
-
?
additional information
?
-
-
the enzyme cleaves and activates CPP32, the precursor of the protease responsible for cleavage of poly(ADPribose)polymerase
-
-
?
additional information
?
-
-
participates in target cell death inflicted by cytotoxic lymphocytes
-
-
?
additional information
?
-
-
induces apoptosis of abnormal cells by cleaving intracellular proteins
-
?
additional information
?
-
-
protects the organism against intracellular infections and cellular transformation, implicated in the generation of tissue damage in a variety of chronic conditions, including autoimmunity and transplant rejection
-
?
additional information
?
-
-
triggers apoptosis in target cells by activating the caspase pathway, implicated in the etiology of rheumatoid arthritis
-
?
additional information
?
-
-
triggers apoptosis in target cells by activating the caspase pathway, implicated in the etiology of rheumatoid arthritis <6>
-
?
additional information
?
-
-
after prolonged incubation, enzyme causes pronounced morphological changes in human tumor cells, leading to partial loss of contact to the culture support
-
-
?
additional information
?
-
-
compared with granzyme B, granzyme A is minor effector of target cell lysis by natural killer cells
-
-
?
additional information
?
-
-
caspases 2, 3 and 7 (C285A mutants) and purified BID are not directly cleaved by GzmH. No activity of GzmH toward Ac-LEHD-7-amino-4-methylcouramin
-
-
?
additional information
?
-
-
granzyme H does not cleave BID or inhibitor of caspase-activated death, does not activate caspases
-
-
?
additional information
?
-
-
Hsp27 is resistant to GrB proteolysis
-
-
?
additional information
?
-
-
granzyme B does not bind membrane phospholipids nor has intrinsic membranolytic properties
-
-
?
additional information
?
-
-
granzyme B has no effect on platelet adhesion and spreading on immobilized collagen. Granzyme B does not cleave glycocalicin (extracellular domain of GPIbalpha)
-
-
?
additional information
?
-
-
mediates cleavage at Asn36 (neo-N terminus: LALLEEIEAENR) in the mouse and at Asp37 (neo-N terminus: LALMEEMEAEHR) in the human DNA polymerase delta catalytic subunit
-
-
?
additional information
?
-
-
tetrapeptide substrate specificity of human GrB: In addition to the requirement for aspartic acid in the P1 position, P4 is specific for Ile, Val, and Leu, whereas P3 and P2 are able to accommodate a wider range of amino acids
-
-
?
additional information
?
-
-
the GrB cleavage sites defined within autoantigens reveal several features: first, all have Ile, Leu, or Val in P4 and are cleaved after the P1 aspartic acid. Second, amino acids in the P2 and P3 positions in autoantigens are almost universally favored by human GrB, but not tolerated by caspases (e.g. proline in P2)
-
-
?
additional information
?
-
-
no substrate: interleukin IL-1beta
-
-
?
additional information
?
-
the enzyme cleaves exracellular matrix proteins, release of active TGF-beta1
-
-
?
additional information
?
-
granzyme B cleaves a highly conserved set of proteins in all three bacteria, i.e. Escherichia coli, Listeria monocytogenes, and Mycobacteria tuberculosis, which function in vital biosynthetic and metabolic pathways that are critical for bacterial survival under diverse environmental conditions. Key proteins required for protein synthesis, folding and degradation are also substrates, including multiple aminoacyl-tRNA synthetases, ribosomal proteins, protein chaperones and the Clp system. GzmB cleaves core metabolic enzymes and disrupts protein synthesis globally. GzmB disrupts Escherichia coli ribosomes (crude ribosomal fraction or purified 70S, 50S and 30S subunits) by cleaving ribosome proteins. GzmB cleaves and inactivates aminoacyl tRNA synthetases. And GzmB disrupts bacterial protein folding and removal of misfolded proteins. Substrate specificity and metabolic effect of granzyme B, overview
-
-
?
additional information
?
-
-
granzyme B cleaves a highly conserved set of proteins in all three bacteria, i.e. Escherichia coli, Listeria monocytogenes, and Mycobacteria tuberculosis, which function in vital biosynthetic and metabolic pathways that are critical for bacterial survival under diverse environmental conditions. Key proteins required for protein synthesis, folding and degradation are also substrates, including multiple aminoacyl-tRNA synthetases, ribosomal proteins, protein chaperones and the Clp system. GzmB cleaves core metabolic enzymes and disrupts protein synthesis globally. GzmB disrupts Escherichia coli ribosomes (crude ribosomal fraction or purified 70S, 50S and 30S subunits) by cleaving ribosome proteins. GzmB cleaves and inactivates aminoacyl tRNA synthetases. And GzmB disrupts bacterial protein folding and removal of misfolded proteins. Substrate specificity and metabolic effect of granzyme B, overview
-
-
?
additional information
?
-
-
many autoantigens are substrates for the protease granzyme B
-
-
?
additional information
?
-
granzyme B (GzmB) is an asp-ase. Granzyme B is a hematopoietic serine protease, which cleaves after negatively charged amino acids. Cleavage specificity analysis using chromogenic and recombinant substrates. Comparisons of GzmB consensus sequences, overview
-
-
?
additional information
?
-
-
granzyme B (GzmB) is an asp-ase. Granzyme B is a hematopoietic serine protease, which cleaves after negatively charged amino acids. Cleavage specificity analysis using chromogenic and recombinant substrates. Comparisons of GzmB consensus sequences, overview
-
-
?
additional information
?
-
human GzmB cleaves only two of the three asp-ase substrates (no activity with acetyl-YVAD-4-nitroanilide) and not the chymase substrate succinyl-AAPF-4-nitroanilide or the two elastase substrates, succinyl-AAPV-4-nitroanilide and succinyl-AAPA-4-nitroanilide. This indicates a broader specificity against different asp-ase substrates for the opossum GzmB compared to human GzmB. Also no activity of the oppossum GznB with N-(tert-butoxycarbonyl)-VLGR-4-nitroanilide (a tryptase substrate), N-benzyloxycarbonyl-GPR-4-nitroanilide (a tryptase substrate), succinyl-AAPI-4-nitroanilide (an elastase substrate), succinyl-AAPL-4-nitroanilide, and succinyl-LLVY-4-nitroanilide (a chymase substrate). Both opossum and human GzmB prefer the rat GzmB consensus sequence. The rat GzmB consensus sequence contains two negatively charged amino acids in the P1 and P3 positions of the substrate. The cleavage of these substrates results in two clearly separated smaller bands, indicating cleavage only at one site in the middle of the linker sequence. Human GzmB cleaves the human substrate sequence (LIGAD-VLVQ) almost as efficiently as the rat GzmB consensus (LIETD-SGL)
-
-
?
additional information
?
-
-
human GzmB cleaves only two of the three asp-ase substrates (no activity with acetyl-YVAD-4-nitroanilide) and not the chymase substrate succinyl-AAPF-4-nitroanilide or the two elastase substrates, succinyl-AAPV-4-nitroanilide and succinyl-AAPA-4-nitroanilide. This indicates a broader specificity against different asp-ase substrates for the opossum GzmB compared to human GzmB. Also no activity of the oppossum GznB with N-(tert-butoxycarbonyl)-VLGR-4-nitroanilide (a tryptase substrate), N-benzyloxycarbonyl-GPR-4-nitroanilide (a tryptase substrate), succinyl-AAPI-4-nitroanilide (an elastase substrate), succinyl-AAPL-4-nitroanilide, and succinyl-LLVY-4-nitroanilide (a chymase substrate). Both opossum and human GzmB prefer the rat GzmB consensus sequence. The rat GzmB consensus sequence contains two negatively charged amino acids in the P1 and P3 positions of the substrate. The cleavage of these substrates results in two clearly separated smaller bands, indicating cleavage only at one site in the middle of the linker sequence. Human GzmB cleaves the human substrate sequence (LIGAD-VLVQ) almost as efficiently as the rat GzmB consensus (LIETD-SGL)
-
-
?
additional information
?
-
no activity with Escherichia coli ClpB protein
-
-
?
additional information
?
-
-
no activity with Escherichia coli ClpB protein
-
-
?
additional information
?
-
-
granzyme B (GzmB) is an asp-ase. Granzyme B is a hematopoietic serine protease, which cleaves after negatively charged amino acids. Cleavage specificity analysis using chromogenic and recombinant substrates. Comparisons of GzmB consensus sequences, overview
-
-
?
additional information
?
-
-
opossum GzmB cleaves all three asp-ase substrates but not the chymase substrate succinyl-AAPF-4-nitroanilide or the two elastase substrates, succinyl-AAPV-4-nitroanilide and succinyl-AAPA-4-nitroanilide. This indicates a broader specificity against different asp-ase substrates for the opossum GzmB compared to human GzmB. Also no activity of the oppossum GznB with N-(tert-butoxycarbonyl)-VLGR-4-nitroanilide (a tryptase substrate), N-benzyloxycarbonyl-GPR-4-nitroanilide (a tryptase substrate), succinyl-AAPI-4-nitroanilide (an elastase substrate), succinyl-AAPL-4-nitroanilide, and succinyl-LLVY-4-nitroanilide (a chymase substrate). The opossum GzmB shows the relatively strict specificity for negatively charged amino acids in the P1 position. Both opossum and human GzmB prefer the rat GzmB consensus sequence. The rat GzmB consensus sequence contains two negatively charged amino acids in the P1 and P3 positions of the substrate. The cleavage of these substrates results in two clearly separated smaller bands, indicating cleavage only at one site in the middle of the linker sequence. The opossum enzyme cleaves the rat consensus substrate (LIETD-SGL) 5-7 times better than the mouse consensus sequence (LIGFD-VGVQ) with almost no cleavage of the human consensus substrate (LIGAD-VLVQ)
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?
additional information
?
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the substrate preference of granzyme B is determined by a positive charge in the specificity pocket
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-
?
additional information
?
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preference for substrates with Glu or Asp as the residue amino-terminal to the scissile bond, little or no activity with oligopeptide substrates for trypsin-like, chymotrypsin-like, and elastase-like proteases
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?
additional information
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involved in cell killing by cytotoxic T lymphocytes, activates the apoptotic death pathway in the target cell
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?
additional information
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involved in cell killing by cytotoxic T lymphocytes, activates the apoptotic death pathway in the target cell
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?
additional information
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proforms of mCASP-2 and mCASP-1 are not substrates, pro-mCASP-6 is not proteolytically cleaved by granzyme B, mCASP-11 and mCASP-12 are not processed
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?
additional information
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requirement for aspartic acid in the substrate P1 position, induces DNA fragmentation in isolated nuclei in the presence of cytosolic factors
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?
additional information
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both human or mouse BID are highly resistant to cleavage by mouse GrB
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?
additional information
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BID is a poor substrate for mouse GzmB. Fails to cleave caspase-8 and ICAD from either human or murine origin. Cleaves nucleophosmin of human origin very inefficiently, does not cleave nucleophosmin within J774 cell free extracts
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?
additional information
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BID is not cleaved
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?
additional information
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both human or mouse BID are highly resistant to cleavage by mouse GrB. It is unable to cleave BID in cell lysates in which caspases are inactivated but induces BID cleavage, albeit inefficiently, in lysates supporting caspase activity. BID pathway is not a prominent primary mediator of the effects of mouse GrB
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?
additional information
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no efficient cleavage of mouse and human Bid by mouse granzyme B
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?
additional information
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platelets from septic granzyme B null (-/-) mice show no lymphotoxicity
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?
additional information
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involved in cell killing by cytotoxic T lymphocytes, activates the apoptotic death pathway in the target cell
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?
additional information
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not able to induce apoptosis on its own
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?
additional information
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processing enzyme, requires extended peptide substrates containing an Asp residue
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?
additional information
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mediates cell death by cytotoxic lymphocytes
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?
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(2S,5S)-4-oxo-5-[[N-(phenylacetyl)-L-isoleucyl]amino]-N-(1H-1,2,3-triazol-4-ylmethyl)-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-carboxamide
-
(2S,5S)-5-[(N-acetyl-L-isoleucyl)amino]-4-oxo-N-(1H-1,2,3-triazol-4-ylmethyl)-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-carboxamide
-
(2S,5S)-5-[[N-(1-benzothiophen-3-ylacetyl)-L-isoleucyl]amino]-4-oxo-N-(1H-1,2,3-triazol-4-ylmethyl)-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-carboxamide
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(2S,5S)-N-((1H-1,2,3-triazol-4-yl)methyl)-5-((3S,4S)-3-(2-(benzo[b]thiophen-3-yl)acetamido)-4-methyl-2-oxohexylamino)-4-oxo-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-carboxamide
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specific granzyme B inhibitor
(3R)-N-cyclopropyl-1-(3-[[(3-methoxyphenyl)sulfonyl]amino]benzoyl)piperidine-3-carboxamide
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(3S)-N-cycloheptyl-3-methyl-1-oxo-2-(pyridin-2-ylmethyl)-10-(1H-pyrrol-1-yl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide
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(5R)-4-(3-methoxybenzyl)-10-methyl-N-(3-methylbutyl)-3-oxo-3,4,5,5a,10,10a-hexahydro-2H-[1,4]thiazepino[7,6-b]indole-5-carboxamide
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(S)-3-((2S,5S)-5-((2S,3S)-2-acetamido-3-methylpentanamido)-4-oxo-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-carboxamido)-4-oxobutanoic acid
100 kDa assembly protein (Ad5-100K)
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no inhibition is seen in mouse or rat
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100K assembly protein of human adenovirus type 5
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potent and specific inhibitor
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2-[(4E)-4-[3-methoxy-4-(prop-2-yn-1-yloxy)benzylidene]-2,5-dioxoimidazolidin-1-yl]-N-(4-methylphenyl)acetamide
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2-[(5E)-5-[4-(2-amino-2-oxoethoxy)-3-methoxybenzylidene]-2,4-dioxo-1,3-thiazolidin-3-yl]-N-(3,4-dimethylphenyl)acetamide
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3-(4-chlorophenyl)-2-([[5-(2,3-dihydro-1,4-benzodioxin-2-yl)-4-phenyl-4,5-dihydro-3H-1,2,4-triazol-3-yl]sulfanyl]methyl)quinazolin-4(3H)-one
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5-[2-(4-chlorophenoxy)ethoxy]-1-cyclohexyl-1H-tetrazole
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Ac-IETD-CHO
reduces activity about 6fold
acetyl-Ile-Ile-Glu-Pro-Asp-aldehyde
granzyme B-specific inhibitor
adenovirus 100K assembly protein
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inhibits gzmB, gzmH relieves gzmB inhibition
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benzyloxycarbonyl-Ala-Ala-Asp-chloromethylketone
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GrB-specific inhibitor. Addition completely blocks reaction with interleukin proIL-18
Bio-x-IEPDp-(Oph)2
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specific and irreversible inhibition both in vitro and in cells
Boc-Ile-Glu-Ala-Asp-CONH(CH2)2-Ph
cytokine response modifier A (CrmA) of poxyvirus
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virally encoded serpin
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engineered chimeric human antichymotrypsin
engineering of a extracellular GrB serpin: a chimeric protein is generated in which the reactive center loop (RCL) of human extracellular antichymotrypsin (ACT) is replaced with that of serpina3n, a mouse extracellular inhibitor of GrB lacking in humans. This serpin contains 27 amino acid residues from the serpina3n RCL and the remaining 395 residues from human ACT. The insertion converts human ACT into a GrB-inhibitory serpin. Several critical residues are identified by scanning mutagenesis on the chimera and serpina3n. Targeted mutagenesis is conducted on wild-type human ACT by specifically substituting those critical residues, creating an inhibitor that contains 99.3% human ACT sequence with only three point mutations. Inhibition kinetics
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guanidinium hydrochloride
Human plasma alpha1-protease inhibitor
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Human plasma alpha2-protease macroglobulin
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hydroxy(6-[2-methoxy-4-[(E)-(3-[2-[(4-methylphenyl)amino]-2-oxoethyl]-2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy]pyridin-3-yl)oxoammonium
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IEPD-CHO
a tetrapeptide aldehyde inhibitor, binding structure analysis from crystal structure, PDB ID 1IAU
IETD-CHO
reduces activity about 6fold
interleukin-10
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granzyme B release from both alloreactive cytotoxic T cell clones and an Epstein-Barr virus-specific cytotoxic T cell clone is inhibited in the presence of interleukin-10 serum
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interleukin-4
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significantly suppresses granzyme B synthesis. Interleukin-4-mediated suppression of granzyme B leads to impaired cytotoxicity of adaptive regulatory T cells against K562 target cells
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L4-100k assembly protein
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acts as a sink that binds to and inhibits granzyme B, preventing target cell death
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Lima-bean trypsin inhibitor
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N-acetyl-L-isoleucyl-L-alpha-glutamyl-N-[(2S)-1-carboxy-3-oxopropan-2-yl]-L-prolinamide
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N-benzyloxycarbonyl-Ile-Glu(-O-methyl)-Thr-Asp(-O-methyl)-fluoromethylketone
i.e. Z-IETD-FMK, specifically and effectively blocks the activity of cattle granzyme B and inhibits the killing of target cells by bovine CD8+ T cells
Nalpha-tert-Butyloxycarbonyl-Ala-Ala-Asp-CH2Cl
PI-9
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granzyme B forms a specific SDS-stable complex with its cognate inhibitor, PI-9
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protease inhibitor-9
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endogenous human inhibitor
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proteinase inhibitor 9 (PI-9)
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serine protease inhibitor 6 (Spi6)
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serine protease inhibitor A3N
i.e. serpin A3N or SA3N, an extracellular inhibitor of GrB possessing multiple biological functions, including the attenuaxadtion of muscular dystrophy in mice, neuropathic pain, and GrB-mediated decorin cleavage and rupture. It also induces neuroprotection in vitro and in vivo. Role of GrB inhibitor SA3N on Escherichia coli LPS-induced inflammation in NK-92 cells. SA3N pretreatment prevents the LPS-induced changes in expression levels of GRP78, CHOP, NF-kappaB, and IkappaBalpha proteins. Also SA3N pretreatment prevents the expression and exocytosis of GrB by LPS
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serpin inhibitor PI-9
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granzyme B specific serpin inhibitor, complexation of enzyme with inhibitor prevents recognition by receptor importin beta and eliminates requirement of importin alpha for nuclear import
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serpin proteinase inhibitor 9
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Soybean trypsin inhibitor
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z-AAD-chloromethylketone
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(S)-3-((2S,5S)-5-((2S,3S)-2-acetamido-3-methylpentanamido)-4-oxo-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-carboxamido)-4-oxobutanoic acid
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(S)-3-((2S,5S)-5-((2S,3S)-2-acetamido-3-methylpentanamido)-4-oxo-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-carboxamido)-4-oxobutanoic acid
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GzmB inhibitor
(S)-3-((2S,5S)-5-((2S,3S)-2-acetamido-3-methylpentanamido)-4-oxo-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-carboxamido)-4-oxobutanoic acid
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peptide-mimetic analog of IEPD-aldehyde
(S)-3-((2S,5S)-5-((2S,3S)-2-acetamido-3-methylpentanamido)-4-oxo-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-carboxamido)-4-oxobutanoic acid
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peptide-mimetic analog of IEPD-aldehyde
Ac-Ile-Glu-Thr-Asp-CHO
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specific granzyme B oligopeptide inhibitor
Ac-Ile-Glu-Thr-Asp-CHO
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specific granzyme B oligopeptide inhibitor
Ac-Ile-Glu-Thr-Asp-CHO
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specific granzyme B oligopeptide inhibitor
antipain
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benzamidine
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Boc-Ile-Glu-Ala-Asp-CONH(CH2)2-Ph
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granB specific inhibitor
Boc-Ile-Glu-Ala-Asp-CONH(CH2)2-Ph
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granB specific inhibitor
Bovine aprotinin
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-
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chymostatin
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EGTA
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inhibits granular granzyme B-mediated killing
guanidinium hydrochloride
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guanidinium hydrochloride
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Human plasma alpha1-protease inhibitor
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-
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Human plasma alpha1-protease inhibitor
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-
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Human plasma alpha2-protease macroglobulin
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Human plasma alpha2-protease macroglobulin
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-
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Lima-bean trypsin inhibitor
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-
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Lima-bean trypsin inhibitor
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-
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Nalpha-tert-Butyloxycarbonyl-Ala-Ala-Asp-CH2Cl
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Nalpha-tert-Butyloxycarbonyl-Ala-Ala-Asp-CH2Cl
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phosphoramidon
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serpina3n
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inhibitor for human and mouse GrB, expressed by Sertoli cells. Inhibitor shares homology with human alpha-1-anti-chymotrypsin
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serpina3n
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inhibitor for human and mouse GrB, expressed by Sertoli cells. Inhibitor shares homology with human alpha-1-anti-chymotrypsin
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Soybean trypsin inhibitor
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-
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Soybean trypsin inhibitor
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additional information
no inhibition by benzyloxycarbonyl-Val-Ala-Asp-(O-methyl)-fluoromethylketone
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additional information
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no inhibition by benzyloxycarbonyl-Val-Ala-Asp-(O-methyl)-fluoromethylketone
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additional information
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zVAD-fmk completely inhibits GzmB induced executioner caspase activity
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additional information
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treatment of T1 cells with pifithrin-alpha results in inhibition of p53 phosphorylation and in a significant decrease in GrB-induced apoptotic T1 cell death. siRNA targeting p53 induces inhibition of streptolysin-O/GrB-mediated apoptotic T1 cell death
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additional information
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inhibition of caspases does not clonogenically rescue cells from human GzmB
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additional information
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natural killer cells stimulated in vitro with interleukin-2 reduce their granzyme H levels over 3-4 days
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additional information
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no significant difference of granzyme B between patients without immunologic treatment and patients after introduction of immunologic treatment, this may be attributed to the variety of clinical stage at the introduction of immunologic treatment and the variety of immunologic treatment
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additional information
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back salt progressively inhibits granzyme B-mediated von Willebrand factor cleavage
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additional information
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induced hypoacetylation in GZMB gene loci by a HAT inhibitor (curcumin) results in decreased expressions of GZMB in memory cells in response to in vitro stimulation
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additional information
structure-based design of non-covalent small molecule inhibitors for human granzyme B via virtual screening strategy employing three constraints and probe sitemapping with FTMAP, usage of crystal structure PDB ID 1FQ3
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additional information
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structure-based design of non-covalent small molecule inhibitors for human granzyme B via virtual screening strategy employing three constraints and probe sitemapping with FTMAP, usage of crystal structure PDB ID 1FQ3
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additional information
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no inhibition with 100K assembly protein of human adenovirus type 5
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additional information
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inhibition of caspases may clonogenically rescue cells from mouse GzmB
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additional information
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to protect beta cells from allogeneic CTL attack, one needs to inhibit the perforin/granzyme and probably also the TNFalpha pathway. Granzyme B-dependent death of NIT-1 cells is not inhibited by Bcl-2 overexpression
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additional information
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no inhibition with 100K assembly protein of human adenovirus type 5
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evolution
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the identification of a granzyme B homologue with aspase (cleaving after aspartic acid) specificity in a non-placental mammal provides strong indications that caspase or Bid-dependent apoptosis by a serine protease with a conserved primary specificity has been part of anti-viral immunity since early mammalian evolution. An asp-ase together with a chymase were the first two serine protease genes to appear in the mammalian chymase locus. The mast cell chymase and GzmB were the first two enzymes to appear in this locus. Granzyme B is the only member of the hematopoietic serine proteases, which cleaves after negatively charged amino acids. Phylogenetic analysis and tree, overview
evolution
the identification of a granzyme B homologue with aspase (cleaving after aspartic acid) specificity in a non-placental mammal provides strong indications that caspase or Bid-dependent apoptosis by a serine protease with a conserved primary specificity has been part of anti-viral immunity since early mammalian evolution. An asp-ase together with a chymase were the first two serine protease genes to appear in the mammalian chymase locus. The mast cell chymase and GzmB were the first two enzymes to appear in this locus. Granzyme B is the only member of the hematopoietic serine proteases, which cleaves after negatively charged amino acids. Phylogenetic analysis and tree, overview
malfunction
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inhibition or downregulation of GrB suppresses bladder cancer cell invasion in vitro
malfunction
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knockout GzmB-/- mice which have a small deletion in the granzyme B gene express granzyme C earlier and more abundantly in lymphocytes on a per-cell basis compared to wild-type, suggesting that the deleted 350-bp region in the granzyme B gene is important for the regulation of both granzymes B and granzyme C. Intraepithelial lymphocytes in GzmB-/- knockout mice likewise express granzyme C
malfunction
the mouse pathogen Brucella microti persists in mice lacking perforin or granzyme B as well as in mice depleted of Tc cells
malfunction
Tresp cells from patients with multiple sclerosis resist Treg suppression via a mechanism that involves GzmB
malfunction
increased circulating granzyme B in type 2 diabetes patients with low-grade systemic inflammation, correlated with unfavorable inflammatory profile, as described by elevated levels of validated adipokines such as interleukin-6, TNF-alpha, and WISP1. Multivariate linear regression analysis shows that increased GrB is associated with type 2 diabetes diagnosis independently from possible confounders
malfunction
inhibition of granzyme B activity blocks inflammation induced by lipopolysaccharide through regulation of endoplasmic reticulum stress signaling in NK92 cells. Inhibition of GrB activity suppresses the changes of NF-kappaB and IkappaBalpha expression levels induced by LPS as part of endoplasmic reticulum stress
malfunction
-
the mouse pathogen Brucella microti persists in mice lacking perforin or granzyme B as well as in mice depleted of Tc cells
-
metabolism
gzmB+ cytotoxic T cell-mediated apoptosis (via phosphatidylserine translocation, mitochondrial depolarization, cytochrome c release, and caspase-3 activation) is severely reduced in 3T9 cells lacking either Bim or both Bak and Bax, gzmB+ cytotoxic T cell-mediated apoptosis is not affected in SV40-transformed mouse embryonic fibroblast cells lacking Bak/Bax.Role of Bim in gzmB-mediated apoptosis, overview
metabolism
-
gzmB+ cytotoxic T cell-mediated apoptosis (via phosphatidylserine translocation, mitochondrial depolarization, cytochrome c release, and caspase-3 activation) is severely reduced in 3T9 cells lacking either Bim or both Bak and Bax, gzmB+ cytotoxic T cell-mediated apoptosis is not affected in SV40-transformed mouse embryonic fibroblast cells lacking Bak/Bax.Role of Bim in gzmB-mediated apoptosis, overview
-
physiological function
-
Granzyme B produced by human plasmacytoid dendritic cells suppresses T-cell proliferation in a GrB-dependent, perforin-independent manner
physiological function
-
granzyme B recoverey is closely correlated with clathriin-dependent endocytosis in NK-92 cells stimulated by target cells (primary porcine endothelial cells)
physiological function
-
GrB plays an important role in inflammatory diseases and cancer. Infiltrating immune cells during chronic inflammation results in elevated levels of GrB to diseased tissue and induces apoptosis in damaged and inflamed areas. Extracellular concentrations of GrB in bodily fluids are elevated in various diseases
physiological function
-
GrB, via extracellular matrix degradation, contributes to the establishment of the urothelial carcinoma invasive phenotype
physiological function
-
gzmB-induced cell death is accompanied by a caspase-dependent pathway of extra-mitochondrial reactive oxygen species production, through activation of NADPH oxidase
physiological function
-
in patients with lupus erythematosus, a correlation between GrB+ lymphocyte and the presence of discoid lupus erythematosus form is found, but in dermatomyositis, GrB is poorly expressed
physiological function
-
increased T cell granzyme b production may contribute to Bronchiolitis obliterans syndrome pathogenesis and is not curtailed by current immunosuppressants
physiological function
-
it is investigated how human perforin enhances GzmB uptake in the cell: perforin activates clathrin- and Dyn-dependent endocytosis to remove perforin from the plasma membrane and enhance GzmB uptake. Both perforin and GzmB are endocytosed into giant endosomal antigen-1 endosomes that form after PFN treatment. When endocytosis is inhibited, sublytic perforin or strptolysin-O becomes lytic, causing necrosis. Consequently, inhibiting clathrin or Dyn pathways shifts the balance of target cell death by GzmB and perforin from apoptosis to necrosis
physiological function
-
TCR/CD28 mediated activation of the PI3K-mTOR pathway is important for granyzme B expression but not proliferation in regulatory T cells
physiological function
-
the effect of T-cell activation on neural progenitor cell (NPC) functions: NPC proliferation and neuronal differentiation are impaired by granzyme B released by the T-cells. GrB mediate its effects by the activation of a Gi-protein-coupled receptor leading to decreased intracellular levels of cAMP and subsequent expression of the voltage-dependent potassium channel, Kv1.3. Blocking channel activity with margatoxin or blocking its expression reverses the inhibitory effects of GrB on neural progenitor cells
physiological function
-
antisense morpholino oligonucleotide knock-down leads to arrest of early development at the 2- to 4-cell stages. Only 11.6% of treated embryos overcome 2-cell arrest and develop into 4-cell stage embryos. Embryos exhibited decreased zygotic gene transcription
physiological function
-
granzyme B-deficient mice, and to a lesser extent perforin-deficient mice, exhibit a significant increase in the number of Ag-specific CD8+ T cells in the lungs and draining lymph nodes of virally infected animals. Viral titers in granzyme B-deficient mice are similar to wild-type mice and significantly less than perforin-deficient mice. Regulatory T cells from wild-type mice express high levels of granzyme B in response to infection, and depletion of regulatory T cells from these mice results in an increase in the number of Ag-specific CD8+ T cells, similar to that observed in granzyme B-deficient mice. Granzyme B-deficient regulatory T cells display defective suppression of CD8+ T cell proliferation in vitro
physiological function
-
granzyme B-mediated processing of IL-1alpha potently enhances the biological activity. Granzyme B does not directly influence inflammatory cytokine production by HeLa or HUVEC cells
physiological function
-
GrB is a potent IL-18 converting enzyme. GrB secreted by CTLs and/or NK cells may initiate IL-18 release from target cells, leading to the development of inflammation
physiological function
-
human neurons are selectively susceptible to granzyme B isolated from cytotoxic T cell granules. In vitro, purified human GrB induces neuronal death to the same extent as the whole activated T cell population. Following internalization through various parts of neurons, GrB accumulates in the neuronal soma. Within the cell body, GrB diffuses out of endosomes possibly through a perforin-independent mechanism and induces subsequent activation of caspases and cleavage of a-tubulin. Inhibition of caspase-3, a substrate for GrB, significantly reduces GrB-mediated neurotoxicity. Treatment of neurons with mannose-6-phosphate prevents GrB entry and inhibits GrB-mediated neuronal death
physiological function
-
in filarial infection with Litomosoides sigmodontis, worm loads are significantly reduced in gzmA/gzmB and in gzmB knockout mice during the whole course of infection, but enhanced only early in gzmA knockout compared with wild-type mice. GzmA/gzmB deficiency is associated with a defense-promoting Th2 cytokine and Ab shift, enhanced early inflammatory gene expression, and a trend of reduced alternatively activated macrophage induction
physiological function
cytotoxic T cells use perforin and granzyme B to kill virus-infected cells and cancer cells. Granzyme B activates the mitochondrial cell death pathway in a Bim-dependent fashion in cytotoxic T lymphocytes
physiological function
in contrast to the intracellular GzmB that mediates apoptosis, GzmB can be found in extracellular fluids where it is hypothesized to regulate other cellular processes. GzmB-induced apoptosis involves the granule-mediated delivery of GzmB into the cytoplasm of target cells. Extracellular enzyme strongly inhibits Treg suppression, without altering Treg viability, nonapoptotic and extracellular activity of granzyme B mediates resistance to regulatory T cell suppression by HLA-DR-CD25hiCD127lo tregs in multiple sclerosis and in response to interleukin-6. The suppression-abrogating cytokine interleukin-6 augments GzmB expression by human CD4 T cells, and it inhibits Treg suppression via this nonapoptotic GzmB-mediated mechanism. DR2CD127lo Tregs stimulated in the presence of extracellular GzmB exhibit reduced expression of the suppression-associated molecules CD39 and PD-L1
physiological function
natural killer cells exhibit cell killing activity that primarily mediated by the pro-apoptotic serine protease granzyme B, which enters targets cells with the help of the pore-forming protein perforin
physiological function
pathogenic extracellular role for GrB in cardiovascular disease, during inflammation, the enzyme accumulates in the extracellular space, retains its activity, and is capable of cleaving extracellular matrix proteins
physiological function
the enzyme granzyme B shows antimalarial activity
physiological function
the enzyme is required for elimination of the mouse pathogen Brucella microti from liver and spleen and is necessary to inhibit Brucella microti replication in primary macrophages
physiological function
the recombinant and native enzyme directly inhibits the growth of human laryngeal cancer Hep-2 cells in vitro and in vivo, respectively
physiological function
-
Asp-ase activity of the Opossum granzyme B supports the role of granzyme B as part of anti-viral immunity
physiological function
Asp-ase activity of the Opossum granzyme B supports the role of granzyme B as part of anti-viral immunity
physiological function
both CD4+ and CD8+ T-cells respond to Listeria monocytogenes, but unlike poorly responding CD4+ T-cells, CD8+ T-cells readily proliferate and express high levels of recombinant chimeric GZMB-Tom as early as 2 days after infection. Using the GZMBTom-OT1 T cells, rapid CD8+ T-cell division and expression of GZMB-Tom following intravenous infection with ActA-/OVA bacteria
physiological function
cytotoxic CD4+ cells have a part in controlling chronic viral infections such as EBV, CMV and HIV, they secrete granzyme B and perforin after pathogen induction. Direct cytotoxicity of parvovirus B19-specific CD4+ cells versus GrB secretion among seven parvovirus B19-seropositive subjects, overview. Pathogenetic role of these B19-specific CD4+ T cells secreting GrB (and possibly IL-17) in autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE)
physiological function
cytotoxic CD8+ T-cells are important mediators of immunity against the bovine intracellular protozoan parasite Theileria parva. Granzyme B is an essential mediator in CD8 T-cell killing of Theileria parva-infected cells. CD8+ T-cell killing of parasitized cells is dependent on granule exocytosis and, specifically, granzyme B. The granzyme B-mediated death of parasitized cells is independent of caspases. Granzyme B activates the proapoptotic molecule Bid. The cytotoxic activity of T-cells is not dependent on caspases but is associated with activation of Bid
physiological function
granzyme B (GrB) is a serine protease produced by some leukocytes, including cytotoxic lymphocytes and macrophages, that exerts both intracellular apoptotic function and extracellular functions, leading to tissue injury, inflammation and repair. Role for GrB in the pathogenesis of several chronic inflammatory diseases
physiological function
granzyme B (GrB) is a serine protease that is expressed in the lytic granules of natural killer (NK) cells and cytotoxic T lymphocytes (CTL), it plays a role in target cell apopxadtosis and a non-cytotoxic role in inflammation
physiological function
granzyme B (GrB) is the initiator of multiple pro-apoptotic pathways and serves as the principle cytotoxic molecule deployed by T cells and natural killer (NK) cells to eliminate target cells. Endogenous GrB is produced as a zymogen bearing an N-terminal Gly-Glu dipeptide that prevents the formation of a functional catalytic triad. Upon packaging into lytic granules inside the immune cell, GrB is processed by the dipeptidyl peptidase cathepsin C (CatC), which cleaves off GrB's Gly-Glu dipeptide and frees the newly N-terminal Ile16 residue to insert into the interior of the molecule and form a salt bridge with Asp194. The resulting conformational change enables the simultaneous generation of an oxyanion hole and maturation of the active-site S1 pocket. Since endogenous GrB is activated prior to its release from the lytic granules of T cells and NK cells, it indiscriminately kills any target cell it enters and does not independently ascertain the identity of the target cell. Target-cell identification is established exclusively at the cell surface via receptor-antigen interactions
physiological function
granzyme B acts against schizont-stage Plasmodium falciparum with IC50 of 0.00159 mM
physiological function
granzyme B disrupts central metabolism and protein synthesis in bacteria to promote an immune cell death program. Granzyme B cleaves a highly conserved set of proteins in all three bacteria, i.e. Escherichia coli, Listeria monocytogenes and Mycobacteria tuberculosis, which function in vital biosynthetic and metabolic pathways that are critical for bacterial survival under diverse environmental conditions. Key proteins required for protein synthesis, folding and degradation are also substrates, including multiple aminoacyl-tRNA synthetases, ribosomal proteins, protein chaperones and the Clp system. Because killer cells use a multi-pronged strategy to target vital pathways, bacteria may not easily become resistant to killer cell attack. The cytotoxic granule pore-forming protein, perforin (PFN), delivers the death-inducing granzyme (Gzm) serine proteases into the target cell, where they cleave multiple substrates to kill the target cell. These cytotoxic cells also kill intracellular bacteria and protozoa. Granzymes A and B (Gzms A and B), the most abundant of the five human Gzms, rapidly trigger oxidative bacterial death by cleaving and disrupting electron transport chain complex I (ETC I), which generates toxic superoxide anions. At the same time, the Gzms degrade bacterial oxidative defense enzymes to disrupt the ability of bacteria to survive oxidative stress. GzmB cleavage of Clp system proteins disrupts the Clp function of removing proteins targeted for degradation
physiological function
intracellular role of Granzyme B (GrB) in immune-mediated cell killing. Enzyme GrB is also implicated in extracellular pathways of inflammation, cytokine activation and autoimmunity
physiological function
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proteolysis by granzyme B (GrB) enhances presentation of autoantigenic peptidylarginine deiminase 4 epitopes in rheumatoid arthritis. Peptidylarginine deiminase 4 (PAD4) is a frequent target of autoantibodies in patients with rheumatoid arthritis (RA) and a substrate for GrB. RA is strongly associated with specific MHC class II alleles. Proteolysis of PAD4 by GrB induced discrete structural changes in PAD4 that promoted enhanced presentation of several immunogenic peptides capable of stimulating PAD4-specific CD4+ T cells from patients with RA. Proteolysis of autoantigens can alter normal MHC class II antigen processing and has been implicated in the induction of autoimmune diseases
physiological function
the serine protease granzyme B (GrB) is produced as an effector molecule and is activated by T and natural killer cells, it specifically targets membrane-bound 70 kDa heat shock protein (mHsp70) on tumor cells, i.e. human tumor cell lines LN229 (glioblastoma), U87 (glioblastoma), HeLa (cervix carcinoma), and H1339 (SCLC), and animal cell lines C6 (rat glioma) and GL261 (glioma). The serine protease granzyme B (GrB) derived from lysates of activated NK cells specifically binds to a sequence of Hsp70 (TKDNNLLGRFELSG, aa450-463) that mediates oligomerization of Hsp70 and is exposed on the cell surface of mHsp70 positive tumor cells. Following binding to mHsp70, GrB is specifically taken up into the cytosol and thereby induces apoptosis in a perforin-independent manner
physiological function
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cytotoxic CD8+ T-cells are important mediators of immunity against the bovine intracellular protozoan parasite Theileria parva. Granzyme B is an essential mediator in CD8 T-cell killing of Theileria parva-infected cells. CD8+ T-cell killing of parasitized cells is dependent on granule exocytosis and, specifically, granzyme B. The granzyme B-mediated death of parasitized cells is independent of caspases. Granzyme B activates the proapoptotic molecule Bid. The cytotoxic activity of T-cells is not dependent on caspases but is associated with activation of Bid
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physiological function
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the enzyme is required for elimination of the mouse pathogen Brucella microti from liver and spleen and is necessary to inhibit Brucella microti replication in primary macrophages
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physiological function
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cytotoxic T cells use perforin and granzyme B to kill virus-infected cells and cancer cells. Granzyme B activates the mitochondrial cell death pathway in a Bim-dependent fashion in cytotoxic T lymphocytes
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physiological function
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both CD4+ and CD8+ T-cells respond to Listeria monocytogenes, but unlike poorly responding CD4+ T-cells, CD8+ T-cells readily proliferate and express high levels of recombinant chimeric GZMB-Tom as early as 2 days after infection. Using the GZMBTom-OT1 T cells, rapid CD8+ T-cell division and expression of GZMB-Tom following intravenous infection with ActA-/OVA bacteria
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additional information
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effects of GrB cleavage on the structure, processing, and immunogenicity of PAD4, overview
additional information
establishment of an enzymatic assay to detect and quantify the expression of functional granzyme B protein. Using this assay, the levels of killing of different Theileria parva-specific CD8+ T-cell clones are found to be significantly correlated with the levels of granzyme B protein but not the levels of mRNA transcript expression. Using inhibitors specific for perforin and granzyme B confirms that CD8+ T-cell killing of parasitized cells is dependent on granule exocytosis and, specifically, granzyme B
additional information
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establishment of an enzymatic assay to detect and quantify the expression of functional granzyme B protein. Using this assay, the levels of killing of different Theileria parva-specific CD8+ T-cell clones are found to be significantly correlated with the levels of granzyme B protein but not the levels of mRNA transcript expression. Using inhibitors specific for perforin and granzyme B confirms that CD8+ T-cell killing of parasitized cells is dependent on granule exocytosis and, specifically, granzyme B
additional information
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establishment of an enzymatic assay to detect and quantify the expression of functional granzyme B protein. Using this assay, the levels of killing of different Theileria parva-specific CD8+ T-cell clones are found to be significantly correlated with the levels of granzyme B protein but not the levels of mRNA transcript expression. Using inhibitors specific for perforin and granzyme B confirms that CD8+ T-cell killing of parasitized cells is dependent on granule exocytosis and, specifically, granzyme B
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D108A
complete loss of enzyme activity
H64A
complete loss of enzyme activity
S203A
complete loss of enzyme activity
A339G
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site-directed mutagenesis
C228F
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fusion protein pro-rGrB-H6, activity with Ac-IEPD-p-nitroanilide substrate as wild-type
C228T
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fusion protein pro-rGrB-H6, activity with Ac-IEPD-p-nitroanilide substrate slightly lower than wild-type
C228V
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fusion protein pro-rGrB-H6, activity with Ac-IEPD-p-nitroanilide substrate slightly lower than wild-type
C335A
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site-directed mutagenesis
C341A
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site-directed mutagenesis
C341S
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site-directed mutagenesis
E340A
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site-directed mutagenesis
E340D
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site-directed mutagenesis
E344A
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site-directed mutagenesis
E344D
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site-directed mutagenesis
F336A
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site-directed mutagenesis
M343A
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site-directed mutagenesis
Q48R/P88A/Y245H
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common allele termed RAH, mutant enzmye has essentially identical proteolytic and cytotoxic properties to wild-type
R226G
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replacing Arg-226 by a glycine yields an enzyme with chymase-like activity cleaving like cathepsin G after Phe
S195A
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GzmH mutant, catalytically inactive
S334A
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site-directed mutagenesis
S345A
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site-directed mutagenesis
T327R
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site-directed mutagenesis
V337A
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site-directed mutagenesis
V338A
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site-directed mutagenesis
R226G
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replacing Arg-226 by a glycine yields an enzyme with chymase-like activity cleaving like cathepsin G after Phe
I99A
substrate acetyl-IEPD-7-amino-4-methylcoumarin, drastic reduction in ratio kcat/Km
I99A/N218A
6fold increase in Km-value, substrate acetyl-IEFD-7-amino-4-methylcoumarin
I99F
substrate acetyl-IEPD-7-amino-4-methylcoumarin, 6fold reduction in ratio kcat/Km
I99R
substrate acetyl-IEPD-7-amino-4-methylcoumarin, 10fold reduction in ratio kcat/Km
N218A
substrate acetyl-IEPD-7-amino-4-methylcoumarin, 30% reduction in ratio kcat/Km
N218A/R192A
substrate acetyl-IEPD-7-amino-4-methylcoumarin, drastic reduction in ratio kcat/Km
N218A/R192E
substrate acetyl-IEPD-7-amino-4-methylcoumarin, drastic reduction in ratio kcat/Km
N218T
substrate acetyl-IEPD-7-amino-4-methylcoumarin, almost 2fold increase in ratio kcat/Km
Y174A
substrate acetyl-IEPD-7-amino-4-methylcoumarin, 6fold reduction in ratio kcat/Km
S183A
inactive mutant
S183A
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no catalytic activity
S183A
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granzyme B active site mutant
additional information
deletion of the activation di-peptide leads to a strong increase in enzyme activity
additional information
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deletion of the activation di-peptide leads to a strong increase in enzyme activity
additional information
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expression of His-tagged enzyme, pro-rGrB-H6, dependent on activation by blood coagulation factor Xa, and of pro(IEPD)-rGrB-H6, engineered for self-activation, and of their C228 mutants
additional information
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expression system for the production of high yields of enzymatic and biologically active human grB by transfection of HEK-293 with grB. The HEK-293 host cells are protected from apoptotic cell death by fusing an inactivation site coupled to a (His)6 tag to the gene sequence of GrB. Inactive grB which is actively released from HEK-293 cells by insertion of a Igkappa leader sequence is purified on a nickel column utilizing the (His)6 tag. After enterokinase digestion and heparin affinity chromatography, high yields of enzymatic and biologically active human grB are obtained
additional information
generation of a recombinant chimeric enzyme by fusion of the pre-pro-granzyme B to the epidermal growth factor receptor peptide ligand transforming growth factor alpha. Activation of the genetically modified natural killer cells by cognate target cells resulted in the release of chimeric enzyme GrB-TGFalpha together with endogenous granzymes and perforin, which augments the effector cells natural cytotoxicity against NK-sensitive tumor cells. The chimeric enzyme GrB-TGFalpha is released into the extracellular space upon induction of degranulation with phspbol-12-myristate-13-acetate and ionomycin. The secreted GrB-TGFalpha chimeric enzyme displays specific binding to EGFR-overexpressing tumor cells, enzymatic activity, and selective target cell killing in the presence of an endosomolytic activity. Release of GrB-TGFalpha protein from NKL/GrB-TGFalpha cells upon activation-induced degranulation
additional information
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generation of a recombinant chimeric enzyme by fusion of the pre-pro-granzyme B to the epidermal growth factor receptor peptide ligand transforming growth factor alpha. Activation of the genetically modified natural killer cells by cognate target cells resulted in the release of chimeric enzyme GrB-TGFalpha together with endogenous granzymes and perforin, which augments the effector cells natural cytotoxicity against NK-sensitive tumor cells. The chimeric enzyme GrB-TGFalpha is released into the extracellular space upon induction of degranulation with phspbol-12-myristate-13-acetate and ionomycin. The secreted GrB-TGFalpha chimeric enzyme displays specific binding to EGFR-overexpressing tumor cells, enzymatic activity, and selective target cell killing in the presence of an endosomolytic activity. Release of GrB-TGFalpha protein from NKL/GrB-TGFalpha cells upon activation-induced degranulation
additional information
construction of a protein-based therapeutic platform, termed cytoplasmic oncoprotein verifier and response trigger (COVERT), which enables the interrogation of intracellular proteases to trigger targeted cytotoxicity. COVERT molecules consist of the cytotoxic protein granzyme B (GrB) fused to an inhibitory N-terminal peptide, which can be removed by researcher-specified proteases to activate GrB function. Fusion of a small ubiquitin-like modifier 1 (SUMO1) protein to GrB yields a SUMO-GrB molecule that is specifically activated by the cancer-associated sentrin-specific protease 1 (SENP1). SUMO-GrB selectively triggers apoptotic phenotypes in HEK293T cells that overexpress SENP1, and it is highly sensitive to different SENP1 levels across cell lines. The rational design of additional COVERT molecules responsive to enterokinase (EK) and tobacco etch virus protease (TEVp) highlight the COVERT platform's modularity and adaptability to diverse protease targets. Primary human T cells (Jurkat cells) can express, package, traffic, and deliver engineered GrB molecules in response to antigen stimulation. The COVERT platform, ENLYFQ-GrB is evaluated for its ability to selectively mediate cytotoxicity against HEK293T cells expressing TEVp. In contrast to SENP1, TEVp is not mammalian in origin, and its forced expression mimics a state of viral infection. Transient expression of GrB in HEK293T cells resulted in marked changes in cell physiology regardless of whether the cells co-expressed TEVp. Method evaluation supporting the modularity and versatility of the COVERT platform for targeting proteolytic markers of a variety of disease states, overview
additional information
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construction of a protein-based therapeutic platform, termed cytoplasmic oncoprotein verifier and response trigger (COVERT), which enables the interrogation of intracellular proteases to trigger targeted cytotoxicity. COVERT molecules consist of the cytotoxic protein granzyme B (GrB) fused to an inhibitory N-terminal peptide, which can be removed by researcher-specified proteases to activate GrB function. Fusion of a small ubiquitin-like modifier 1 (SUMO1) protein to GrB yields a SUMO-GrB molecule that is specifically activated by the cancer-associated sentrin-specific protease 1 (SENP1). SUMO-GrB selectively triggers apoptotic phenotypes in HEK293T cells that overexpress SENP1, and it is highly sensitive to different SENP1 levels across cell lines. The rational design of additional COVERT molecules responsive to enterokinase (EK) and tobacco etch virus protease (TEVp) highlight the COVERT platform's modularity and adaptability to diverse protease targets. Primary human T cells (Jurkat cells) can express, package, traffic, and deliver engineered GrB molecules in response to antigen stimulation. The COVERT platform, ENLYFQ-GrB is evaluated for its ability to selectively mediate cytotoxicity against HEK293T cells expressing TEVp. In contrast to SENP1, TEVp is not mammalian in origin, and its forced expression mimics a state of viral infection. Transient expression of GrB in HEK293T cells resulted in marked changes in cell physiology regardless of whether the cells co-expressed TEVp. Method evaluation supporting the modularity and versatility of the COVERT platform for targeting proteolytic markers of a variety of disease states, overview
additional information
creation and synthesis of an antimalarial fusion protein consisting of granzyme B fused to a merozoite surface protein 4 (MSP4)-specific single-chain Fv protein (scFv), which targets the enzyme to infected erythrocytes, with up to an 8fold reduction in the IC50 of 176 nM compared to wild-type granzyme B against schizont-stage Plasmodium falciparum strain 3D7A, method, overview. Generation of a single-chain variable fragment (scFv) from an MSP4EGF-like domain-specific murine antibody, 2.44IgG1
additional information
synthesis of the GrB-superparamagnetic nanocarriers (SPIONs): preparation of superparamagnetic iron oxide nanoparticles from salt solutions FeSO4 and FeCl3 by coprecipitation, dextran is added to the nanosuspension for prevention of sedimentation. The dextran coating of the synthesized nanoparticles is cross-linked with epichlorohydrin and aminated. Activated by carbodiimide aminated-dextran is coupled to the carboxyl groups of proteins. The hydrodynamic size and electrophoretic properties of the nanoparticles are estimated. Functionalized superparamagnetic iron oxide nanoparticles (SPIONs) have emerged as potential clinical tools for cancer theranostics. GrB-functionalized SPIONs act as a contrast enhancement agent for magnetic resonance imaging and induce specific tumor cell apoptosis. Combinatorial regimens employing stereotactic radiotherapy and/or magnetic targeting are found to further enhance the therapeutic efficacy of GrB-SPIONs in different tumor mouse models. Magnetic targeting of the nanoparticles in vivo with a magnet placed on top of orthotopic U87 glioblastoma in NMRU nu/nu mice and C6 glioma in Wistar rats drastically enhances the accumulation of nanoparticles to the location of the magnet
additional information
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deletion of the DNase1 hypersensitive site upstream of the granzyme B gene results in a 10fold reduction in expression
additional information
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granzyme A/B-deficient mice exhibit significantly reduced survival compared to wild-type mice. Granzyme B-deficient mice clear both allogeneic and syngeneic tumor cell lines more efficiently than do wild-type mice. NK and CD8+ T cell death in tumor ascites of granzyme B-deficient mice is reduced after Treg cell depletion
additional information
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granzyme B deficient mice lack expression of linked granzyme-loci, due to accidental effects of the thymidine kinase enhancer integrated into the granzyme locus on mouse Chromosome 14
additional information
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granzyme B-deficient mice possess a normal phenotype, with the exception of reduced CTL-mediated target cell apoptosis, antiviral responses, and tumor cell clearance. Treg cells from granzyme B-deficient mice can not suppress immune responses as effectively as Treg cells from wild-type mice. Granzyme B-deficient recipient mice exhibit reduced allograft vasculopathy and increased susceptibility to allgergen-induced asthma. Hearts from 129J donor mice transplanted into granzyme B-KO mice exhibit significantly smaller lesions and luminal narrowing compared with wild-type recipients
additional information
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gzmB-/-CTL cells, no cleavage of Bid
additional information
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gzmB-deficient mice do not cause cell death in susceptible adherent target cells
additional information
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mice deficient in granzyme B are up to 100000fold more sensitive to the natural mouse proxivirus pathogen ectromelia than are wild-type mice
additional information
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target cells with reduced levels of Hsp70/Hsp90-organizing protein are no more susceptible than control target cells to GzmB-/-/deltaPGK-neo and GzmB-/-/+PGK-neo natural killer effectors. GzmA-/- x GzmB-/-/deltaPGK-neo and GzmA-/- x GzmB-/-/+PGK-neo doubly deficient natural killer effectors, likewise, show no differences in susceptibility between control and Hsp70/Hsp90-organizing protein knockdown target cells
additional information
construction of functional fluorescent chimeric GZMB-Tomato (GZMB-Tom) fusion protein. The GZMB-Tom knock-in mice in which GZMB-Tom faithfully reproduce GZMB expression, provide useful tools to dissect mechanisms leading to the development of anti-bacterial effector and memory CD8+ T-cells and reactivation of the memory response to cognate antigen or inflammatory signals. The use of CD8+ T-cells from knock in mice expressing a functional fluorescent chimeric GZMB-Tom protein in place of GZMB allow the evaluation of the induction of GZMB during CD8+ T-cell differentiation as a function of T-cell division. Mice homozygous for GZMB-Tom and heterozygous for the OT1 (GZMB-Tom-OT1) or OT2 (GZMB-Tom-OT2) transgenic T-cell receptors are used. Congenic C57BL/6 (CD45.1) mice are used as recipients
additional information
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granzyme A/B-deficient mice exhibit significantly reduced survival compared to wild-type mice. Granzyme B-deficient mice clear both allogeneic and syngeneic tumor cell lines more efficiently than do wild-type mice. NK and CD8+ T cell death in tumor ascites of granzyme B-deficient mice is reduced after Treg cell depletion
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additional information
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construction of functional fluorescent chimeric GZMB-Tomato (GZMB-Tom) fusion protein. The GZMB-Tom knock-in mice in which GZMB-Tom faithfully reproduce GZMB expression, provide useful tools to dissect mechanisms leading to the development of anti-bacterial effector and memory CD8+ T-cells and reactivation of the memory response to cognate antigen or inflammatory signals. The use of CD8+ T-cells from knock in mice expressing a functional fluorescent chimeric GZMB-Tom protein in place of GZMB allow the evaluation of the induction of GZMB during CD8+ T-cell differentiation as a function of T-cell division. Mice homozygous for GZMB-Tom and heterozygous for the OT1 (GZMB-Tom-OT1) or OT2 (GZMB-Tom-OT2) transgenic T-cell receptors are used. Congenic C57BL/6 (CD45.1) mice are used as recipients
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biotechnology
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engineering of mutant enzyme suitable for cleavage of fusion proteins
diagnostics
increased detection of the enzyme in cytotoxic T lymphocytes and natural killer cells are an immune signature for lymphocyte activation in hemophagocytic lymphohistiocytosis, irrespective of genetic subtype, and may also be a useful measure of immune activation in other related conditions
synthesis
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expression system for the production of high yields of enzymatic and biologically active human grB by transfection of HEK-293 with grB. The HEK-293 host cells are protected from apoptotic cell death by fusing an inactivation site coupled to a (His)6 tag to the gene sequence of GrB. Inactive grB which is actively released from HEK-293 cells by insertion of a Igkappa leader sequence is purified on a nickel column utilizing the (His)6 tag. After enterokinase digestion and heparin affinity chromatography, high yields of enzymatic and biologically active human grB are obtained
analysis
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caution in the design and interpretation of experiments using GrBs from different species due to distinct tetrapeptide specificities and abilities to recruit the BID pathway
analysis
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caution in the design and interpretation of experiments using GrBs from different species due to distinct tetrapeptide specificities and abilities to recruit the BID pathway
degradation
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human and murine GzmB are distinct enzymes with different substrate preferences. Subtle differences in enzyme structure can radically affect substrate selection. Caspases are essential for apoptosis initiated by mouse GzmB
degradation
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human and murine GzmB are distinct enzymes with different substrate preferences. Subtle differences in enzyme structure can radically affect substrate selection. Caspases are not essential for apoptosis initiated by human GzmB
medicine
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cytolytic T-lymphocytes from enzyme or granzyme A deficient mice similarly induce early proapoptotic features such as phosphatidyl serine exposure on plasma membrane, or reactive oxygen radical generation, though with distinct kinetics. Cytolytic T-lymphocytes from granzyme A, but not granzyme B deficient animals activate caspase 3 and 9. All granzyme-induced apoptotic features depend critically on perforin
medicine
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A streptolysin-O/GrB combination results in the induction of p53 accumulation and transcriptional activity associated with strong induction of apoptotic cell death in T1 cells
medicine
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activated mast cells contribute, via secreted gzmB, to cell death, increased vascular permeability, leukocyte extravasation and subsequent inflammatory processes in affected tissues. GzmB-induced detachment of adherent mouse embryonic fibroblasts leads to anoikis. GzmB induces a disorganization of endothelial cell-cell contacts
medicine
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can induce rapid apoptosis of target cells, which is dependent on caspase activation and mitochondrial damage. GzmH-induced death is characterized by phosphatidylserine externalization, nuclear condensation, DNA fragmentation, caspase activation and cytochrome c release. GzmH may play an essential role in caspase-dependent pathogen clearance in the innate immunity that may complement the proapoptotic function of GzmB in human natural killer cells
medicine
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detection of target GzB activity followed by caspase 3 activation provides a unique readout of a potentially lethal injury delivered by cytotoxic lymphocytes
medicine
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ELISPOT measurements of granzyme B permit the identification of actively ongoing CD8+ cell responses. Importance for immune diagnostic of infections, transplantation, allergies, autoimmune diseases, tumors and vaccine development
medicine
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expression of granzyme B by peripheral CD8+ T lymphocytes does not vary between emphysematous smokers, smokers and non-smokers with normal lung function
medicine
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extension of the present standard of IFN-gamma measurements to the analysis of GzB and perforin release in functional T cell assays will provide new insights into CD8+ effector T cell function in HIV infection
medicine
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granzyme B may play a key role in ateromatous diseases. Role in cardiac allograft vasculopathy and atherosclerosis
medicine
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granzyme B may play a key role in ateromatous diseases. Role in cardiac allograft vasculopathy and atherosclerosis
medicine
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granzyme B plays a role in the cytotoxic response in lichen planus. It is a probable target for future immunomodulator therapy
medicine
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granzyme H participates in the anti-adenovirus response by both inhibiting virus replication directly and simultaneously re-sensitizing infected cell to granzyme B-induced cell death
medicine
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granzymes can mediate antiviral activity through direct cleavage of viral substrates. Different granzymes have synergistic functions to outflank viral defenses that block host antiviral activities
medicine
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GrB proteolysis of Hsc70/Hsp70-interacting protein is important to the efficiency of death induction
medicine
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GzmH induces cell death, it is nearly as potent as GzmB. Exhibits an alternative cell death pathway in innate immunity. In contrast to GzmB, GzmH achieves cell death by acting on mitochondrial and nuclear targets but not through the activation of hallmark apoptotic substrates
medicine
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Hsp70/Hsp90-organizing protein per se does not set the threshold for susceptibility to GzmB-induced apoptosis
medicine
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key role of plasticity in the granzyme B mediated cell death pathway in the killing of changed tumor cells, resulting in keratoacanthoma regression through apoptosis or direct damage of tumor cells. Insufficient activation of cytotoxic T lymphocytes and decreased release or activity of granzyme B may be responsible for squamous cell-carcinoma progression and occasional aggressive behavior in keratoacanthomas. Targeted delivery of granzyme B to squamous cell, carcinoma cells may be a new agent that may have an additive or synergic effect with conventional therapeutic modalities, since there are still no known cellular resistance mechanisms capable of protecting cells against all granzyme B mediated pathways
medicine
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pleiotropic pro-apoptotic function of gzmB presumably to counteract evasion strategies of pathogens and to control tumors
medicine
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Treg cells derived from the tumor environment can induce NK and CD8(+) T cell death in a granzyme B- and perforin-dependent fashion. Granzyme B and perforin are relevant for Treg cell-mediated suppression of tumor clearance in vivo
medicine
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extracellular granzyme B may help control localized coagulation during inflammation
medicine
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granzyme B level may contribute to a diagnosis of immune-mediated epilepsy including Rasmussen syndrome
medicine
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granzyme B may be the limiting factor in adaptive regulatory T cell-mediated K562 target cell killing
medicine
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plasma granzyme B level on day 14 is a significant predicting factor for left ventricular remodeling after acute myocardial infarction
medicine
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platelets are lymphotoxic effectors in sepsis via granzyme B
medicine
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potential role for granzyme B in the process of initiation of myasthenia gravis
medicine
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the release of granzyme B through two routes from unconjugated cytotoxic lymphocytes suggests that it functions outside the cell and may contribute to pathology in cases of immune dysregulation, such as familial hemophagocytic lymphohistiocytosis
medicine
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granzyme B GrB labels a subpopulation of effector cells involved in ongoing cytotoxic action should be considered as a specific marker showing the extent of the direct local cytotoxic damage in patients with lupus erythematosus
medicine
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modified versions of GzmB with lower isoelectric points can be utilized without loss of apoptosis-inducing potential but fewer side activities
medicine
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since GzmB is very effective in killing human tumor cell lines that are resistant against cytotoxic drugs GrzmB is used as an effector domain in potential immunoconjugates
medicine
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both GzmA and GzmB levels are significantly increased in serum of patients with patients with amyotrophic lateral sclerosis. There is a significant correlation of serum GzmB levels with severity of clinical state of amyotrophic lateral sclerosis patients
medicine
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granzyme B-deficient mice, and to a lesser extent perforin-deficient mice, exhibit a significant increase in the number of Ag-specific CD8+ T cells in the lungs and draining lymph nodes of virally infected animals. Viral titers in granzyme B-deficient mice are similar to wild-type mice and significantly less than perforin-deficient mice. Regulatory T cells from wild-type mice express high levels of granzyme B in response to infection, and depletion of regulatory T cells from these mice results in an increase in the number of Ag-specific CD8+ T cells, similar to that observed in granzyme B-deficient mice. Granzyme B-deficient regulatory T cells display defective suppression of CD8+ T cell proliferation in vitro
medicine
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human neurons are selectively susceptible to granzyme B isolated from cytotoxic T cell granules. In vitro, purified human GrB induces neuronal death to the same extent as the whole activated T cell population. Following internalization through various parts of neurons, GrB accumulates in the neuronal soma. Within the cell body, GrB diffuses out of endosomes possibly through a perforin-independent mechanism and induces subsequent activation of caspases and cleavage of a-tubulin. Inhibition of caspase-3, a substrate for GrB, significantly reduces GrB-mediated neurotoxicity. Treatment of neurons with mannose-6-phosphate prevents GrB entry and inhibits GrB-mediated neuronal death
medicine
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internalization of grB by membrane Hsp70 positive tumor cells is dependent on mammalian glycosylation of GrB. Neuraminic acid blocks binding of GrB to CT26 tumor cells
medicine
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ischemic brain samples after stroke contain significantly higher levels of Gra-b and interferon-gamma inducible protein-10 than non-ischemic controls. In stroke, poly(ADP-ribose) polymerase-1 and heat shock protein-70 are cleaved to canonical proteolytic signature fragments by Gra-b. Gra-b also binds to Bid and caspase-3 and colocalizesw with Annexin-V+/TUNEL+ in degenerating neurons. Gra-b inhibition protects both normal and ischemia-reperfused neurons against in vitro neurotoxicity mediated by activated CG-SH cells and supernatants. Increased leukocyte infiltration and elevated Gra-b levels in the post-stroke brain can induce contact-dependent and independent post-ischemic neuronal death to aggravate stroke injury
medicine
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proinflammatory gzmA and anti-inflammatory gzmB are novel modulators of the Th1/2 balance and defense in helminth infection
medicine
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the precursor frequency and cytotoxic lymphocyte activity of HLA-A2-restricted transaldolase 168-176-specific CD8+ T cells is increased in multiple sclerosis patients. The major C-terminal GrB cleavage product of transaldolase, residues 28-337, has no enzymatic activity but retains the antigenicity of full-length transaldolase, effectively stimulating the proliferation and cytotoxic lymphocyte activity of peripheral blood mononuclear cells and of CD8+ T cell lines from patients with multiple sclerosis. Sera of multiple sclerosis patients exhibit similar binding affinity to wild-type and GrB-cleaved transaldolase
medicine
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The soluble granzyme B levels are higher in systemic lupus erythematosus patients and associated with various clinical features like reduced complement components, C3 and C4, and skin lesion. The soluble granzyme B levels are also sturdily related with severity of the disease. Excessive secretion of soluble granzyme B and enhanced activity of cytotoxic T lymphocyte may play a vital role in the pathogenesis of systemic lupus erythematosus and organ damage
medicine
the protease may be a therapeutic target for the prevention of bacterial sepsis without affecting immune control of the pathogen
medicine
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Treg cells derived from the tumor environment can induce NK and CD8(+) T cell death in a granzyme B- and perforin-dependent fashion. Granzyme B and perforin are relevant for Treg cell-mediated suppression of tumor clearance in vivo
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medicine
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the protease may be a therapeutic target for the prevention of bacterial sepsis without affecting immune control of the pathogen
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pharmacology
granzyme B has antimalarial activity against Plasmodium falciparum strain 3D7A of 1600 nM and can be targeted delivered by a granzyme B-single-chain Fv fusion protein, inhibitory activities on parasite growth of different fusion proteins on two different Plasmodium falciparum strains, overview
pharmacology
antimalarial activity of granzyme B and its targeted delivery by a granzyme B-single-chain Fv fusion protein. Therapeutic efficacies of recombinant antibody-mediated antimalarial immunotherapeutics based on granzyme B, overview
pharmacology
functionalized superparamagnetic iron oxide nanoparticles (SPIONs) have emerged as potential clinical tools for cancer theranostics. GrB-functionalized SPIONs act as a contrast enhancement agent for magnetic resonance imaging and induce specific tumor cell apoptosis. Combinatorial regimens employing stereotactic radiotherapy and/or magnetic targeting are found to further enhance the therapeutic efficacy of GrB-SPIONs in different tumor mouse models. GrB-SPIONs accumulate in the tumor and increase MR contrast enhancement. The therapeutic potential of a systemic administration of GrB-SPIONs is evaluated in o.t. xenograft H1339 lung cancer model with and without brain metastases and U87 glioma mouse models, overview
additional information
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cytotoxic granule-mediated death of both primary and transformed beta cells requires granzyme B. Early cell death is completely dependent on granzyme B. Death induced by granzyme B is dependent on cosecretion with perforin
additional information
Equine granzyme B shows close proximity to putative equine mast cell protease and to granzyme B from mouse, rat, and human. Equine granzyme B may be useful in the development of immunological assays for the activity of equine lymphocytes
additional information
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Equine granzyme B shows close proximity to putative equine mast cell protease and to granzyme B from mouse, rat, and human. Equine granzyme B may be useful in the development of immunological assays for the activity of equine lymphocytes
additional information
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role for granzyme B as mediator in mast cell biology
additional information
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role for granzyme B in the dismantling of the cytoskeleton. In the execution phase of apoptosis it may modify key structural proteins thus enabling the cell to be properly dismantled and eliminated by phagocytosis
additional information
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ability of gzmH to cleave host proteins involved in essential viral functions provides a novel mechanism by which granzymes can mediate direct antiviral activities