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Information on EC 3.4.21.B26 - proprotein convertase 5
for references in articles please use BRENDA:EC3.4.21.B26
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preliminary BRENDA-supplied EC number
EC Tree 3 Hydrolases
3.4 Acting on peptide bonds (peptidases)
3.4.21 Serine endopeptidases
3.4.21.B26 proprotein convertase 5
The enzyme appears in viruses and cellular organisms
- 3.4.21.B26
- furin
-
subtilisin-like
- medicine
- endoproteases
-
pcsks
-
furin-like
Reaction Schemes
showcleavage at the RX(K/R)R consensus motif. Release of mature proteins from their proproteins by cleavage of Arg-Xaa-Yaa-Arg-/-Zaa bonds, where Xaa can be any amino acid and Yaa is Arg or Lys.
Synonyms
pc5/6, pcsk5, pc5/6a, pc5-a, proprotein convertase 5/6, prohormone convertase 5, pc5-b, proprotein convertase subtilisin/kexin type 5, pc5/6b, proprotein convertase 5, more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
PC5
PC5-A
PC5-B
PC5/6
PC5/6A
PC5/6B
proprotein convertase 5/6 (PC5/6) has two splice variants: soluble PC5/6A and membrane-bound PC5/6B
PC5A
PC6
PCSK5
proprotein convertase 5/6
proprotein convertase PC5/6
PC5/6A
proprotein convertase 5/6 (PC5/6) has two splice variants: soluble PC5/6A and membrane-bound PC5/6B
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
cleavage at the RX(K/R)R consensus motif. Release of mature proteins from their proproteins by cleavage of Arg-Xaa-Yaa-Arg-/-Zaa bonds, where Xaa can be any amino acid and Yaa is Arg or Lys.
-
-
-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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CAS REGISTRY NUMBER
COMMENTARY
99676-46-7
-
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
2-aminobenzoic acid-SKKRKRRFLG-(3-nitro)-Tyr-A + H2O
2-aminobenzoic acid-SKKRKRR + FLG-(3-nitro)-Tyr-A
-
Substrates: fluorogenic substrate encompassing the processing site of envelope glycoproteins of respiratory syncytial virus
Products: -
Products: -
?
2-aminobenzoyl-GGRRTRREAI-(3-nitro)-Tyr-A + H2O
2-aminobenzoyl-GGRRTRR + EAI-(3-nitro)-Tyr-A
-
Substrates: fluorogenic substrate encompassing the processing site of envelope glycoproteins of ebola virus
Products: -
Products: -
?
2-aminobenzoyl-RNTPRERKKRGL-(3-nitro)-Tyr-A + H2O
2-aminobenzoyl-RNTPRERKKR + GL-(3-nitro)-Tyr-A
-
Substrates: -
Products: -
Products: -
?
2-aminobenzoyl-RNTPRERRRKKRGL-(3-nitro)-Tyr-A + H2O
2-aminobenzoyl-RNTPRERRRKKR + GL-(3-nitro)-Tyr-A
-
Substrates: fluorogenic substrate encompassing the processing site of envelope glycoproteins of Hong Kong virus
Products: -
Products: -
?
2-aminobenzoyl-RNTPRKKRGL-(3-nitro)-Tyr-A + H2O
2-aminobenzoyl-RNTPRKKR + GL-(3-nitro)-Tyr-A
-
Substrates: -
Products: -
Products: -
?
2-aminobenzoyl-RNTPRRRKKRGL-(3-nitro)-Tyr-A + H2O
2-aminobenzoyl-RNTPRRRKKR + GL-(3-nitro)-Tyr-A
-
Substrates: -
Products: -
Products: -
?
2-aminobenzoyl-SKKRKRRFLG-(3-nitro)-Tyr-A + H2O
2-aminobenzoyl-SKKRKRR + FLG-(3-nitro)-Tyr-A
-
Substrates: -
Products: -
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?
ANKKPPLPKRVRRQIHATPTP + H2O
ANKKPPLPKRVRR + QIHATPTP
Substrates: a peptide representing alpha-dystroglycan amino acids 299-319 that encompasses the predicted PC6-cleavage site (ANKKPPLPKRVRR312-/-QIHATPTP)
Products: -
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?
human immunodeficiency virus type 1 Vpr + H2O
?
Substrates: undergoes proteolytic processing at a very well conserved proprotein convertase cleavage site, R85QRR88-/-, proprotein convertases PC5 and PACE4 can efficiently process extracellular Vpr
Products: -
Products: -
?
PCSK9 + H2O
PCSK9-DELTAN218 + ?
Substrates: PC5/6A inactivates PCSK9 by cleavage at the motif RFHR218
Products: -
Products: -
?
pGlu-Arg-Thr-Lys-Arg-methyl-7-amido-4-methylcoumarin + H2O
?
-
Substrates: -
Products: -
Products: -
?
preprohepcidin + H2O
?
Substrates: key role of the convertases furin, PACE4, PC5 and/or PC7 in the generation and secretion of active hepcidin
Products: -
Products: -
?
pro-cocaine- and amphetamine-regulated transcript precursor + H2O
bioactive pro-cocaine- and amphetamine-regulated transcript I + bioactive pro-cocaine- and amphetamine-regulated transcript II + ?
Substrates: PC5/6A preferentially cleaves the pairs of basic sites, KR/KK, of the CART precursor isoforms
Products: -
Products: -
?
pro-integrin-alpha5 + H2O
active integrin-alpha5 + ?
Substrates: cleavage of the substrate into its heavy and light chains
Products: -
Products: -
?
pro-integrin-alphaV + H2O
active integrin-alphaV + ?
Substrates: cleavage of the substrate into its heavy and light chains
Products: -
Products: -
?
pro-von Willebrand factor + H2O
von Willebrand factor + ?
-
Substrates: -
Products: -
Products: -
?
proform bone morphogenetic protein-2 + H2O
mature bone morphogenetic protein-2 + ?
Substrates: -
Products: -
Products: -
?
proform platelet-derived growth factor A + H2O
mature platelet-derived growth factor A + ?
protein tyrosine phosphatase kappa + H2O
?
-
Substrates: the enzyme cleaves the ectodomain of protein tyrosine phosphatase kappa
Products: -
Products: -
?
pyro-ERTKR-7-amido-4-methylcoumarin + H2O
pyro-ERTKR + 7-amino-4-methylcoumarin
-
Substrates: -
Products: -
Products: -
?
pyroglutamic acid-RTKR-7-amido-4-methylcoumarin + H2O
pyroglutamic acid-RTKR + 7-amino-4-methylcoumarin
Substrates: -
Products: -
Products: -
?
receptor protein tyrosine phosphatase + H2O
?
Substrates: -
Products: -
Products: -
?
Val-Gln-Arg-Glu-Lys-Arg-Ala-Val-Gly-Leu + H2O
?
-
Substrates: both isoforms are capable of processing the junction between gp120 and gp41 within the HIV-1 gp160 precursor
Products: -
Products: -
?
alpha-dystroglycan + H2O
?
Substrates: cleavage site (ANKKPPLPKRVRR312-/-QIHATPTP). Full-length alpha-dystroglycan in the human endometrial epithelium is a barrier for embryo attachment and removal of the N-terminus by proprotein convertase 5/6 regulates receptivity. Removal of alpha-dystroglycan N-terminus is an important posttranslational control of endometrial receptivity and uterine fluid
Products: -
Products: -
?
alpha-dystroglycan + H2O
?
Substrates: cleavage site (ANKKPPLPKRVRR312-/-QIHATPTP)
Products: -
Products: -
?
osteopontin + H2O
?
Substrates: Pcsk5/PCSK5 is temporally and spatially expressed with Opn/OPN (Spp1/SPP1) in osteoblasts and osteocytes, indicating that osteopontin could be a physiologically relevant substrate for PC5/6 or PC5/6-activated proteases in bone. Cleavage of osteopontin may modify the function of osteopontin in bone and/or modulate other enzymatic cleavages of osteopontin, leading to alterations in the bone phenotype
Products: -
Products: -
?
osteopontin + H2O
?
Substrates: the enzyme (PC5/6A) efficiently and completely cleaves human osteopontin into three distinct fragments migrating at about 50 kDa, about 18 kDa, and 16 kDa, with evidence for the predicted cleavage sites being at 168RSKSKKFR175-/- and 241KQSR244-/-. PC5/6 also partially cleaves mouse osteopontin to release fragments of about 30 kDa and 29 kDa
Products: -
Products: -
?
proform platelet-derived growth factor A + H2O
mature platelet-derived growth factor A + ?
Substrates: activation, the substrate is localized specifically to the apical surface of the luminal and glandular epithelium of uterine endometrium in the receptive phase, but barely detectable in the non-receptive phase
Products: -
Products: -
?
proform platelet-derived growth factor A + H2O
mature platelet-derived growth factor A + ?
Substrates: activation
Products: -
Products: -
?
additional information
?
-
-
Substrates: both isoforms can cleave a number of fluorogenic substrates of general formula Arg/Lys-(Xaa)n-(Arg)-, where n= 2, 4, or 6
Products: -
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?
additional information
?
-
-
Substrates: substrate cleavage analysis. Strong preference of Arg at position P1 and P4
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Products: -
?
additional information
?
-
Substrates: development of a high-throughput immunohistochemic assay for human proprotein convertase 5/6 for detecting uterine receptivity, method evaluation, overview
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Products: -
?
additional information
?
-
-
Substrates: development of a high-throughput immunohistochemic assay for human proprotein convertase 5/6 for detecting uterine receptivity, method evaluation, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: no substrate: amyloid-beta precursor protein
Products: -
Products: -
?
additional information
?
-
Substrates: death at birth of the PC5/6-deficient embryos
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Products: -
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
alpha-dystroglycan + H2O
?
Substrates: cleavage site (ANKKPPLPKRVRR312-/-QIHATPTP). Full-length alpha-dystroglycan in the human endometrial epithelium is a barrier for embryo attachment and removal of the N-terminus by proprotein convertase 5/6 regulates receptivity. Removal of alpha-dystroglycan N-terminus is an important posttranslational control of endometrial receptivity and uterine fluid
Products: -
Products: -
?
human immunodeficiency virus type 1 Vpr + H2O
?
Substrates: undergoes proteolytic processing at a very well conserved proprotein convertase cleavage site, R85QRR88-/-, proprotein convertases PC5 and PACE4 can efficiently process extracellular Vpr
Products: -
Products: -
?
osteopontin + H2O
?
Substrates: Pcsk5/PCSK5 is temporally and spatially expressed with Opn/OPN (Spp1/SPP1) in osteoblasts and osteocytes, indicating that osteopontin could be a physiologically relevant substrate for PC5/6 or PC5/6-activated proteases in bone. Cleavage of osteopontin may modify the function of osteopontin in bone and/or modulate other enzymatic cleavages of osteopontin, leading to alterations in the bone phenotype
Products: -
Products: -
?
preprohepcidin + H2O
?
Substrates: key role of the convertases furin, PACE4, PC5 and/or PC7 in the generation and secretion of active hepcidin
Products: -
Products: -
?
pro-integrin-alpha5 + H2O
active integrin-alpha5 + ?
Substrates: cleavage of the substrate into its heavy and light chains
Products: -
Products: -
?
pro-integrin-alphaV + H2O
active integrin-alphaV + ?
Substrates: cleavage of the substrate into its heavy and light chains
Products: -
Products: -
?
proform bone morphogenetic protein-2 + H2O
mature bone morphogenetic protein-2 + ?
Substrates: -
Products: -
Products: -
?
proform platelet-derived growth factor A + H2O
mature platelet-derived growth factor A + ?
Substrates: activation, the substrate is localized specifically to the apical surface of the luminal and glandular epithelium of uterine endometrium in the receptive phase, but barely detectable in the non-receptive phase
Products: -
Products: -
?
protein tyrosine phosphatase kappa + H2O
?
-
Substrates: the enzyme cleaves the ectodomain of protein tyrosine phosphatase kappa
Products: -
Products: -
?
additional information
?
-
Substrates: death at birth of the PC5/6-deficient embryos
Products: -
Products: -
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Alpha1-proteinase inhibitor
-
inhibits cleavage of Val-Gln-Arg-Glu-Lys-Arg-Ala-Val-Gly-Leu
-
PC5-specific antisense oligonucleotide-1
inhibits PC activity and consequently av cleavage
PC5-specific antisense oligonucleotide-2
inhibits PC activity and consequently av cleavage, most potent inhibitor
decanoyl-Arg-Val-Lys-Arg-chloromethylketone
decreases enzyme activity and expression
decanoyl-Arg-Val-Lys-Arg-chloromethylketone
0.05 mM inhibits PC activity and consequently av cleavage
additional information
PC5 protein expression is reduced in the presence of PC5-1 and PC5-2 pSUPER siRNA vectors
-
additional information
-
PC5 protein expression is reduced in the presence of PC5-1 and PC5-2 pSUPER siRNA vectors
-
additional information
av cleavage not inhibited by the MMP-inhibitor GM6001 and PC5-specific antisense oligonucleotide-3
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
significant increase in PC5/6 mRNA levels in endometrial stromal cells treated with 17beta-estradiol plus medroxyprogesterone acetate during decidualization, whereas 17beta-estradiol alone has no effect
-
additional information
-
significant increase in PC5/6 mRNA levels in endometrial stromal cells treated with 17beta-estradiol plus medroxyprogesterone acetate during decidualization, whereas 17beta-estradiol alone has no effect
-
additional information
the activation of PC5A is stimulated by incubation of Y1 cells with adrenocorticotropic hormone or 8-Br-cAMP
-
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Adenocarcinoma
The proprotein convertase PC5/6 is protective against intestinal tumorigenesis: in vivo mouse model.
Anorectal Malformations
Anorectal atresia and variants at predicted regulatory sites in candidate genes.
Anorectal Malformations
PCSK5 and GDF11 Expression in the Hindgut Region of Mouse Embryos with Anorectal Malformations.
Anorectal Malformations
Pcsk5 is required in the early cranio-cardiac mesoderm for heart development.
Anorectal Malformations
Spatiotemporal expression of proprotein convertase subtilisin/kexin type 5 in the development of anorectal malformations in fetal rats.
Anus, Imperforate
Pcsk5 is required in the early cranio-cardiac mesoderm for heart development.
Atherosclerosis
Proprotein convertases in human atherosclerotic plaques: the overexpression of FURIN and its substrate cytokines BAFF and APRIL.
Breast Neoplasms
Tumor-Suppressor Inactivation of GDF11 Occurs by Precursor Sequestration in Triple-Negative Breast Cancer.
Carcinogenesis
The proprotein convertase PC5/6 is protective against intestinal tumorigenesis: in vivo mouse model.
Cardiovascular Diseases
Genetic variation at the proprotein convertase subtilisin/kexin type 5 gene modulates high-density lipoprotein cholesterol levels.
Cardiovascular Diseases
Inactivation of endothelial proprotein convertase 5/6 decreases collagen deposition in the cardiovascular system: role of fibroblast autophagy.
Colonic Neoplasms
Galectin-3 binding protein promotes cell motility in colon cancer by stimulating the shedding of protein tyrosine phosphatase kappa by proprotein convertase 5.
Endometrial Neoplasms
Proprotein convertases in post-menopausal endometrial cancer: Distinctive regulation and non-invasive diagnosis.
Esophageal Atresia
Pcsk5 is required in the early cranio-cardiac mesoderm for heart development.
Influenza in Birds
Crystal structure of inhibitor-bound human MSPL that can activate high pathogenic avian influenza.
Nasal Polyps
Proprotein Convertase 5/6A is Associated with BMP-2-induced Squamous Cell Differentiation.
Neoplasm Metastasis
Implications of Proprotein Convertases in Ovarian Cancer Cell Proliferation and Tumor Progression: Insights for PACE4 as a Therapeutic Target.
Neoplasm Metastasis
Tumor-Suppressor Inactivation of GDF11 Occurs by Precursor Sequestration in Triple-Negative Breast Cancer.
Neoplasms
Alterations in gene expression of proprotein convertases in human lung cancer have a limited number of scenarios.
Neoplasms
Comprehensive characterization of the alternative splicing landscape in head and neck squamous cell carcinoma reveals novel events associated with tumorigenesis and the immune microenvironment.
Neoplasms
Galectin-3 binding protein promotes cell motility in colon cancer by stimulating the shedding of protein tyrosine phosphatase kappa by proprotein convertase 5.
Neoplasms
Implications of Proprotein Convertases in Ovarian Cancer Cell Proliferation and Tumor Progression: Insights for PACE4 as a Therapeutic Target.
Neoplasms
Liver-Specific Inactivation of the Proprotein Convertase FURIN Leads to Increased Hepatocellular Carcinoma Growth.
Neoplasms
Proprotein convertases in post-menopausal endometrial cancer: Distinctive regulation and non-invasive diagnosis.
Neoplasms
The proprotein convertase PC5/6 is protective against intestinal tumorigenesis: in vivo mouse model.
Neuroinflammatory Diseases
Activation of proprotein convertase in the mouse habenula causes depressive-like behaviors through remodeling of extracellular matrix.
Pheochromocytoma
PC5-A-mediated processing of pro-neurotensin in early compartments of the regulated secretory pathway of PC5-transfected PC12 cells.
Takayasu Arteritis
Genome-wide association study identifies susceptibility loci in IL6, RPS9/LILRB3, and an intergenic locus on chromosome 21q22 in Takayasu's arteritis.
Tracheoesophageal Fistula
Pcsk5 is required in the early cranio-cardiac mesoderm for heart development.
Vaccinia
Cellular localization and role of prohormone convertases in the processing of pro-melanin concentrating hormone in mammals.
Vaccinia
Processing of prothyrotropin-releasing hormone by the family of prohormone convertases.
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000226
Ac-Arg-Arg-Arg-Tle-Lys-Arg-AMC
non-purified enzyme preparation, pH 7, 24°C
-
0.0038
Ac-Arg-Arg-Tle-Arg-Arg-AMC
non-purified enzyme preparation, pH 7, 24°C
-
0.000442
Ac-Arg-Arg-Tle-Lys-Arg-AMC
non-purified enzyme preparation, pH 7, 24°C
-
0.00244
Ac-Arg-Arg-Tyr-Lys-Arg-AMC
non-purified enzyme preparation, pH 7, 24°C
-
0.00153
Ac-Arg-Arg-Val-Lys-Arg-AMC
non-purified enzyme preparation, pH 7, 24°C
-
0.0178
Ac-Arg-Val-Arg-Arg-AMC
non-purified enzyme preparation, pH 7, 24°C
-
0.000651
H-Arg-Arg-Arg-Tle-Lys-Arg-AMC
non-purified enzyme preparation, pH 7, 24°C
-
0.000586
H-Arg-Arg-Tle-Lys-Arg-AMC
non-purified enzyme preparation, pH 7, 24°C
-
0.00964
Phac-Arg-Tle-Arg-Arg-AMC
non-purified enzyme preparation, pH 7, 24°C
-
0.00263
Phac-Arg-Tle-Lys-Arg-AMC
non-purified enzyme preparation, pH 7, 24°C
-
0.0112
Phac-Arg-Val-Arg-Arg-AMC
non-purified enzyme preparation, pH 7, 24°C
-
0.00635
Phac-Arg-Val-Lys-Arg-AMC
non-purified enzyme preparation, pH 7, 24°C
-
0.0071
Pyr-Arg-Thr-Lys-Arg-AMC
non-purified enzyme preparation, pH 7, 24°C
-
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000265
D-Arg-Arg-Arg-Arg-Arg-Arg
-
in 20 mM Bis-Tris, pH 6.5, 1 mM CaCl2, at 37°C
0.000019
D-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg
-
in 20 mM Bis-Tris, pH 6.5, 1 mM CaCl2, at 37°C
0.00043
L-Arg-Arg-Arg-Arg-Arg-Arg
-
in 20 mM Bis-Tris, pH 6.5, 1 mM CaCl2, at 37°C
0.000575
L-Arg-Arg-Arg-Arg-Arg-Arg-Arg
-
in 20 mM Bis-Tris, pH 6.5, 1 mM CaCl2, at 37°C
0.00045
L-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg
-
in 20 mM Bis-Tris, pH 6.5, 1 mM CaCl2, at 37°C
0.00015
L-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg
-
in 20 mM Bis-Tris, pH 6.5, 1 mM CaCl2, at 37°C
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
expressed during mouse development in many tissues including bone and tooth
brenda
-
in the small intestine PC5/6 is mainly expressed in enterocytes
brenda
-
PC5 is limited to the glia and the retina of the optic nerve head
brenda
-
PC5 is limited to the glia and the retina of the optic nerve head
brenda
expressed in the telencephalon at embryonic day E15.5
brenda
expressed during mouse development in many tissues including bone and tooth
brenda
additional information
the enzyme is up-regulated in the human endometrium specifically at the time of epithelial receptivity
brenda
high enzyme expression level during receptive phase
brenda
up-regulation of PC5 in proliferating cell nuclear antigen-positive vascular smooth muscle cells following balloon injury
brenda
additional information
NCI-H146 cell line, NCI-H345 cell line, NCI-A520 cell line, LoVo-C5 cell line, BON-1 cell line
brenda
additional information
PC5 is 6fold increased in decidualized uterine horn, independent of embryo implantation, whereas it is low to undetectable in control hormone-primed nondecidualized uterine horn
brenda
additional information
-
PC5 is 6fold increased in decidualized uterine horn, independent of embryo implantation, whereas it is low to undetectable in control hormone-primed nondecidualized uterine horn
brenda
additional information
-
first bronchial arch, wall of bulbus cordis, the nasal pit and pituitary, alphaT3-1 cell line, betaT3-1 cell line, AfT-20 cell line, CT26 cell line, CG-2 cell line, TM3-cell line, Ltk cell line and ES cell line
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
the endometrial PC6 is secreted into the uterine fluid
-
brenda
PC5A is complexed to its prosegment at the plasma membrane
brenda
-
the membrane-bound isoform is mostly expressed in intestine and kidney
brenda
proprotein convertase 5/6 (PC5/6) has two splice variants: soluble PC5/6A and membrane-bound PC5/6B
brenda
proprotein convertase 5/6 (PC5/6) has two splice variants: soluble PC5/6A and membrane-bound PC5/6B
-
brenda
Highest Expressing Human Cell Lines
Cell Line LinksPlease wait a moment until the data is sorted. This message will disappear when the data is sorted.
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
evolution
the enzyme is a serine protease of the proprotein convertase family
evolution
the enzyme belongs to the Ca2+-dependent proprotein convertase family of enzymes
malfunction
-
gene inactivation of PC5/6 leads to lethality at birth, the lack of PC5/6 in enterocytes results in a significantly higher tumor number in the duodenum, the absence of PC5/6 is also associated with a premature mortality of ApcMin/+ mice that harbor a heterozygote multiple intestinal neoplasia mutation in the adenomatous polyposis coli gene
malfunction
specific lentiviral short hairpin RNA-mediated PC5/6A knockdown decreases bone morphogenetic protein-2 expression and maturation, decreases expression of squamous cell markers, and increases expression of ciliated cell markers. Enzyme inhibition by decanoyl-Arg-Val-Lys-Arg-chloromethylketone and bone morphogenetic protein receptor inhibition by LDN-193189 suppress squamous differentiation, promote mucociliary differentiation, and down-regulate the BMP-2/Smad1/5/8/p38 signaling pathways
malfunction
enzyme-knockout endometrial epithelial cells show reduced capacity to attach to trophoblast spheroids and bind to fibronectin compared with control. Knockdown of the enzyme decreases cell surface presentation of functional integrins-alpha1, alpha2, alpha5, alphaV and alphaVbeta5
malfunction
PC5/6-knockout mouse embryos show developmental abnormalities, and reduced overall mineralization
malfunction
PC6 knockdown reduces removal of alpha-dystroglycan N-terminus from endometrial epithelial cell surface and blastocyst adhesion
metabolism
the enzyme is the proprotein convertase that is tightly regulated in the uterus during embryo implantation
metabolism
the enzyme in the human endometrium is tightly regulated during receptivity for embryo implantation
physiological function
-
the proprotein convertase PC5/6 is protective against intestinal tumorigenesis
physiological function
involvement of the enzyme in squamous differentiation of human nasal epithelial cells possibly through up-regulation of the BMP-2/pSmad1/5/8/p38 signaling pathway
physiological function
proprotein convertase 5/6 cleaves and activates platelet-derived growth factor A in the human endometrium in preparation for embryo implantation, overview. The enzyme plays an important role in converting precursor proteins into their active forms through specific proteolysis
physiological function
the enzyme is critical for receptivity establishment in women, endometrial enzyme is secreted into the uterine fluid, and levels correlate with receptivity status
physiological function
pro-integrins-alpha in the endometrial epithelium are post-translationally cleaved by the enzyme into functional subunits for the binding of blastocyst and adhesion of extracellular matrix proteins, the enzyme is responsible for the post-translational cleavage of pro-integrin-alpha5 and integrin-alphaV into their heavy and light chains in HEC-1-A cells. The integrins are transmembrane glycoproteins, some of which play an important role in the adhesive interactions between the trophoblast (blastocyst) and uterine epithelium at implantation
physiological function
Pcsk5/PCSK5 is temporally and spatially expressed with Opn/OPN (Spp1/SPP1) in osteoblasts and osteocytes, indicating that osteopontin could be a physiologically relevant substrate for PC5/6 or PC5/6-activated proteases in bone. Cleavage of osteopontin may modify the function of osteopontin in bone and/or modulate other enzymatic cleavages of osteopontin, leading to alterations in the bone phenotype
physiological function
full-length alpha-dystroglycan in the human endometrial epithelium is a barrier for embryo attachment and removal of the N-terminus by proprotein convertase 5/6 regulates receptivity. Removal of alpha-dystroglycan N-terminus is an important posttranslational control of endometrial receptivity and uterine fluid
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). PCSK5_MOUSE
1877
0
209257
Swiss-Prot
Secretory Pathway (Reliability: 2)
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
117000
126000
Western blot analysis, proform in decidualized endometrial stromal cells
65000
117000
Western blot analysis, mature form in decidualized endometrial stromal cells
117000
-
SDS-PAGE, soluble PC5 isolated from the medium of GH4-C1 cells infected with the vaccinia virus recombinant
65000
Western blot analysis, C-terminally truncated form in decidualized endometrial stromal cells
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
proteolytic modification
-
COOH-terminal cleavage of the membrane-bound PC5-B occurs along the secretory pathway, intracellular zymogen cleavage of pro-PC5-A
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
stable knockout of the enzyme in HEC-1-A cells by specific siRNA
additional information
-
stable knockout of the enzyme in HEC-1-A cells by specific siRNA
additional information
-
Pcsk5delta4-deficient allele missing exon 4 that encodes the catalytic Asp173, delta4/delta4 genotype is embryonic lethal, heterozygote mice are healthy and fertile
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
Mono Q HR column chromatography, HIC 6FF column chromatography, and Superdex 200 gel filtration
-
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
real-time RT-PCR enzyme expression analysis in wild-type and enzyme knockout HEC-1-A cells
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
decanoyl-Arg-Val-Lys-Arg-chloromethylketone decreases enzyme activity and expression
the enzyme is up-regulated in the human endometrium specifically at the time of epithelial receptivity
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
PC5/6 plays a key role for decidualization in human endometrium and its action is necessary for prolactin production from endometrial stromal cells
medicine
av endoproteolytic activation is necessary for integrin-mediated adhesion and migration as well as signaling and requires PC5 in vascular smooth muscle cells
medicine
carotid atherosclerotic lesions obtained by endaterectomy contain PC5, PC5 colocalizes with av integrin
medicine
-
crucial role in heart development and in endothelial cells, involved in embryonic bone morphogenesis
medicine
-
crucial role in prorenin activation within the adrenal cortex or in HIV gp160 processing in CD4+ cells, major impact on cellular proliferation and on sexual differentiation, involvement in food metabolism
medicine
PC5 is a potential contributor to the initiation, progression, and complications of atherosclerosis and restenosis, targeting PC5 will likely provide novel anti-atherosclerosis strategies
medicine
PC5 is a potential contributor to the initiation, progression, and complications of atherosclerosis and restenosis, targeting PC5 will likely provide novel anti-atherosclerosis strategies
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Basak, A.; Zhong, M.; Munzer, J.S.; Chretien, M.; Seidah, N.G.
Implication of the proprotein convertases furin, PC5 and PC7 in the cleavage of surface glycoproteins of Hong Kong, Ebola and respiratory syncytial viruses: a comparative analysis with fluorogenic peptides
Biochem. J.
353
537-545
2001
Mus musculus
brenda
De Strooper, B.; Creemers, J.W.; Moechars, D.; Huylebroeck, D.; Van De Ven, W.J.; Van Leuven, F.; Van den Berghe, H.
Amyloid precursor protein is not processed by furin, PACE 4, PC1/3, PC2, PC4 and PC5/6 of the furin family of proprotein processing enzymes
Biochim. Biophys. Acta
1246
185-188
1995
Mus musculus
brenda
De Bie, I.; Marcinkiewicz, M.; Malide, D.; Lazure, C.; Nakayama, K.; Bendayan, M.; Seidah, N.G.
The isoforms of proprotein convertase PC5 are sorted to different subcellular compartments
J. Cell. Biol.
135
1261-1275
1996
Mus musculus
brenda
Stawowy, P.; Kallisch, H.; Veinot, J.P.; Kilimnik, A.; Prichett, W.; Goetze, S.; Seidah, N.G.; Chretien, M.; Fleck, E.; Graf, K.
Endoproteolytic activation of av integrin by proprotein convertase PC5 is required for Vascular smooth muscle cell adhesion to vitronectin and integrin-dependent signaling
Circulation
109
770-776
2004
Homo sapiens (Q92824), Rattus norvegicus (P41413)
brenda
Tang, M.; Mikhailik, A.; Pauli, I.; Giudice, L.C.; Fazelabas, A.T.; Tulac, S.; Carson, D.D.; Kaufman, D.G.; Barbier, C.; Creemers, J.W.; Tabibzadeh, S.
Decidual differentiation of stromal cells promotes proprotein convertase 5/6 expression and lefty processing
Endocrinology
146
5313-5320
2005
Mus musculus (Q04592), Mus musculus
brenda
Seidah, N.G.; Chretien, M.
Proprotein convertase 5
Handbook of Proteolytic Enzymes (Barrett, A. J. , Rawlings, N. D. , Woessner, J. F. , Eds. ) Academic Press
2
1874-1877
2004
Mus musculus, Rattus norvegicus, Homo sapiens
-
brenda
Okada, H.; Nie, G.; Salamonsen, L.A.
Requirement for proprotein convertase 5/6 during decidualization of human endometrial stromal cells in vitro
J. Clin. Endocrinol. Metab.
90
1028-1034
2005
Homo sapiens (Q92824), Homo sapiens
brenda
Stawowy Philip, S.P.; Fleck Eckar, F.E.
Proprotein convertases furin and PC5: targeting atherosclerosis and restenosis at multiple levels
J. Mol. Med.
83
865-875
2005
Homo sapiens (Q92824), Rattus norvegicus (P41413)
brenda
Essalmani, R.; Hamelin, J.; Marcinkiewicz, J.; Chamberland, A.; Mbikay, M.; Chretien, M.; Seidah, N.G.; Prat, A.
Deletion of the gene encoding proprotein convertase 5/6 causes early embryonic lethality in the mouse
Mol. Cell. Biol.
26
354-361
2006
Homo sapiens (Q92824), Mus musculus
brenda
Stein, J.; Shah, R.; Steiner, D.F.; Dey, A.
RNAi-mediated silencing of prohormone convertase (PC) 5/6 expression leads to impairment in processing of cocaine- and amphetamine-regulated transcript (CART) precursor
Biochem. J.
400
209-215
2006
Mus musculus (Q04592)
brenda
Dikeakos, J.D.; Mercure, C.; Lacombe, M.; Seidah, N.G.; Reudelhuber, T.L.
PC1/3, PC2 and PC5/6A are targeted to dense core secretory granules by a common mechanism
FEBS J.
274
4094-4102
2007
Mus musculus
brenda
Seidah, N.G.; Mayer, G.; Zaid, A.; Rousselet, E.; Nassoury, N.; Poirier, S.; Essalmani, R.; Prat, A.
The activation and physiological functions of the proprotein convertases
Int. J. Biochem. Cell Biol.
40
1111-1125
2008
Mus musculus (Q04592)
brenda
Benjannet, S.; Rhainds, D.; Hamelin, J.; Nassoury, N.; Seidah, N.G.
The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications
J. Biol. Chem.
281
30561-30572
2006
Homo sapiens (Q92824), Homo sapiens
brenda
Mayer, G.; Hamelin, J.; Asselin, M.; Pasquato, A.; Marcinkiewicz, E.; Tang, M.; Tabibzadeh, S.; Seidah, N.G.
The regulated cell surface zymogen activation of the proprotein convertase PC5A directs the processing of its secretory substrates
J. Biol. Chem.
283
2373-2384
2008
Mus musculus (Q04592)
brenda
Fugere, M.; Appel, J.; Houghten, R.A.; Lindberg, I.; Day, R.
Short polybasic peptide sequences are potent inhibitors of PC5/6 and PC7: use of positional scanning-synthetic peptide combinatorial libraries as a tool for the optimization of inhibitory sequences
Mol. Pharmacol.
71
323-332
2007
Homo sapiens
brenda
Reynolds Nicole , R.N.; Blum Aliss, B.A.; Kitagawa Kouk, K.K.; Beinfeld, M.C.
Inhibition of PC5 expression decreases CCK secretion and increases PC2 expression
Peptides
27
901-904
2006
Mus musculus (Q04592), Mus musculus
brenda
Padua, M.B.; Hansen, P.J.
Regulation of DNA synthesis and the cell cycle in human prostate cancer cells and lymphocytes by ovine uterine serpin
BMC Cell Biol.
9
5
2008
Mus musculus (Q04592)
brenda
Remacle, A.G.; Shiryaev, S.A.; Oh, E.S.; Cieplak, P.; Srinivasan, A.; Wei, G.; Liddington, R.C.; Ratnikov, B.I.; Parent, A.; Desjardins, R.; Day, R.; Smith, J.W.; Lebl, M.; Strongin, A.Y.
Substrate cleavage analysis of furin and related proprotein convertases. A comparative study
J. Biol. Chem.
283
20897-20906
2008
Homo sapiens
brenda
Essalmani, R.; Zaid, A.; Marcinkiewicz, J.; Chamberland, A.; Pasquato, A.; Seidah, N.G.; Prat, A.
In vivo functions of the proprotein convertase PC5/6 during mouse development: Gdf11 is a likely substrate
Proc. Natl. Acad. Sci. USA
105
5750-5755
2008
Mus musculus (Q04592), Mus musculus
brenda
Xiao, Y.; Chen, G.; Richard, J.; Rougeau, N.; Li, H.; Seidah, N.G.; Cohen, E.A.
Cell-surface processing of extracellular human immunodeficiency virus type 1 Vpr by proprotein convertases
Virology
372
384-397
2008
Mus musculus (Q04592)
brenda
Fuller, J.A.; Brun-Zinkernagel, A.M.; Clark, A.F.; Wordinger, R.J.
Subtilisin-like proprotein convertase expression, localization, and activation in the human retina and optic nerve head
Invest. Ophthalmol. Vis. Sci.
50
5759-5768
2009
Homo sapiens
brenda
Sun, X.; Essalmani, R.; Seidah, N.G.; Prat, A.
The proprotein convertase PC5/6 is protective against intestinal tumorigenesis: in vivo mouse model
Mol. Cancer
8
73
2009
Mus musculus
brenda
Kim, Y.S.; Jung, J.A.; Kim, H.J.; Ahn, Y.H.; Yoo, J.S.; Oh, S.; Cho, C.; Yoo, H.S.; Ko, J.H.
Galectin-3 binding protein promotes cell motility in colon cancer by stimulating the shedding of protein tyrosine phosphatase kappa by proprotein convertase 5
Biochem. Biophys. Res. Commun.
404
96-102
2011
Homo sapiens
brenda
Fritzsche, J.; Stawowy, P.
Time for endothelial cell proprotein convertase PC5/6 in cardiovascular medicine?
J. Mol. Med.
89
1061-1063
2011
Mus musculus
brenda
Lee, S.N.; Lee, D.H.; Lee, M.G.; Yoon, J.H.
Proprotein convertase 5/6A is associated with BMP-2-induced squamous cell differentiation
Am. J. Respir. Cell Mol. Biol.
52
749-761
2014
Homo sapiens (Q92824), Homo sapiens
brenda
Heng, S.; Dynon, K.; Li, Y.; Edgell, T.; Walton, K.; Rombauts, L.J.; Vollenhoven, B.; Nie, G.
Development of a high-throughput assay for human proprotein convertase 5/6 for detecting uterine receptivity
Anal. Biochem.
475
14-21
2015
Homo sapiens (Q92824), Homo sapiens
brenda
Paule, S.; Aljofan, M.; Simon, C.; Rombauts, L.J.; Nie, G.
Cleavage of endometrial alpha-integrins into their functional forms is mediated by proprotein convertase 5/6
Hum. Reprod.
27
2766-2774
2012
Homo sapiens (Q92824), Homo sapiens
brenda
Paule, S.; Nebl, T.; Webb, A.; Vollenhoven, B.; Rombauts, L.; Nie, G.
Proprotein convertase 5/6 cleaves platelet-derived growth factor A in the human endometrium in preparation for embryo implantation
Mol. Hum. Reprod.
21
262-270
2014
Homo sapiens (Q92824), Homo sapiens
brenda
Hoac, B.; Susan-Resiga, D.; Essalmani, R.; Marcinkiweicz, E.; Seidah, N.G.; McKee, M.D.
Osteopontin as a novel substrate for the proprotein convertase 5/6 (PCSK5) in bone
Bone
107
45-55
2018
Mus musculus (Q04592)
brenda
Heng, S.; Paule, S.G.; Li, Y.; Rombauts, L.J.; Vollenhoven, B.; Salamonsen, L.A.; Nie, G.
Posttranslational removal of alpha-dystroglycan N terminus by PC5/6 cleavage is important for uterine preparation for embryo implantation in women
FASEB J.
29
4011-4022
2015
Homo sapiens (Q92824), Homo sapiens
brenda
Lam van, T.V.; Ivanova, T.; Lindberg, I.; Boettcher-Friebertshaeuser, E.; Steinmetzer, T.; Hardes, K.
Design, synthesis, and characterization of novel fluorogenic substrates of the proprotein convertases furin, PC1/3, PC2, PC5/6, and PC7
Anal. Biochem.
655
114836
2022
Homo sapiens (Q92824)
brenda
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