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Information on EC 3.4.21.112 - site-1 protease
for references in articles please use BRENDA:EC3.4.21.112
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EC Tree 3 Hydrolases
3.4 Acting on peptide bonds (peptidases)
3.4.21 Serine endopeptidases
3.4.21.112 site-1 protease
IUBMB Comments
Cleaves sterol regulatory element-binding proteins (SREBPs) and thereby initiates a process by which the active fragments of the SREBPs translocate to the nucleus and activate genes controlling the synthesis and uptake of cholesterol and unsaturated fatty acids into the bloodstream . The enzyme also processes pro-brain-derived neurotrophic factor and undergoes autocatalytic activation in the endoplasmic reticulum through sequential cleavages . The enzyme can also process the unfolded protein response stress factor ATF6 at an Arg-His-Lys-Lys┼ site [4,8], and the envelope glycoprotein of the highly infectious Lassa virus [5,8] and Crimean Congo hemorrhagic fever virus at Arg-Arg-Lys-Lys┼ [7,8]. Belongs in peptidase family S8A.
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
- 3.4.21.112
-
srebps
- proprotein
- furin
-
site-2
- atf6
-
subtilase
-
lassa
- arenaviruses
- medicine
-
cleavage-activating
-
mbtps1
-
nonbasic
-
crimean-congo
-
mucolipidosis
- glcnac-1-phosphotransferase
-
n-acetylglucosamine-1-phosphotransferase
- degradation
Reaction Schemes
showprocesses precursors containing basic and hydrophobic/aliphatic residues at P4 and P2, respectively, with a relatively relaxed acceptance of amino acids at P1 and P3
Synonyms
ski-1, ski-1/s1p, site-1 protease, site 1 protease, pcsk8, hski-1, convertase site 1 protease, srebp site 1 protease, subtilisin kexin isozyme 1/site 1 protease, subtilisin-kexin isoenzyme-1, more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
membrane-bound transcription factor site-1 protease
PCSK8
protease responsible for activating sigmaW
PrsW
S1P
site-1 protease
SKI-1
SKI-1/S1P
subtilisin kexin isozyme-1/site-1 protease
S1P
-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
processes precursors containing basic and hydrophobic/aliphatic residues at P4 and P2, respectively, with a relatively relaxed acceptance of amino acids at P1 and P3
-
-
-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
cleavage of C-N-linkage
hydrolysis of peptide bond
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CAS REGISTRY NUMBER
COMMENTARY
167140-48-9
-
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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-Asp-Ile-Tyr-Ile-Ser-Arg-Arg-Leu-Leu-Gly-Thr-Phe-Thr-(3-nitro)Tyr-Ala + H2O
2-aminobenzoic acid-Asp-Ile-Tyr-Ile-Ser-Arg-Arg-Leu-Leu + Gly-Thr-Phe-Thr-(3-nitro)Tyr-Ala
-
Substrates: cleaves between Leu and Gly
Products: -
Products: -
?
2-aminobenzoic acid-Asp-Ile-Tyr-Ile-Ser-Arg-Arg-Leu-Leu-Gly-Thr-Phe-Thr-3-nitrotyrosyl-Ala-CONH2 + H2O
2-aminobenzoic acid-Asp-Ile-Tyr-Ile-Ser-Arg-Arg-Leu-Leu + Gly-Thr-Phe-Thr-3-nitrotyrosyl-Ala-CONH2
-
Substrates: -
Products: -
Products: -
?
2-aminobenzoic acid-SSGSRRLLSEESY(NO2)-Ala-NH2 + H2O
?
-
Substrates: -
Products: -
Products: -
?
2-aminobenzoyl-ALVLRKPLFLDSY(NO2)-Ala + H2O
?
-
Substrates: cleaves between Leu and Phe
Products: -
Products: -
?
2-aminobenzoyl-Arg-Asn-Thr-Pro-Arg-Arg-Glu-Arg-Arg-Arg-Lys-Lys-Arg-Gly-Leu-(3-nitro)Tyr-Ala + H2O
2-aminobenzoyl-Arg-Asn-Thr-Pro-Arg-Arg-Glu-Arg-Arg-Arg-Lys-Lys-Arg-Gly-Leu + (3-nitro)Tyr-Ala
-
Substrates: cleaves between Leu and 3-nitrotyrosine
Products: -
Products: -
?
2-aminobenzoyl-Arg-His-Ser-Ser-Arg-Arg-Leu-Leu-Arg-Ala-Ile-(3-nitro)Tyr-Ala + H2O
2-aminobenzoyl-Arg-His-Ser-Ser-Arg-Arg-Leu-Leu + Arg-Ala-Ile-(3-nitro)Tyr-Ala
-
Substrates: cleaves between Leu and Arg
Products: -
Products: -
?
2-aminobenzoyl-Arg-Ser-Leu-Lys-Tyr-Ala-Glu-Ser-Asp-(3-nitro)-Tyr-Ala + H2O
2-aminobenzoyl-Arg-Ser-Leu-Lys + Tyr-Ala-Glu-Ser-Asp-(3-nitro)-Tyr-Ala
-
Substrates: cleaves between Lys and Tyr
Products: -
Products: -
?
2-aminobenzoyl-Ser-Arg-Arg-Leu-Leu-Arg-Ala-Leu-Glu-(3-nitro)Tyr-Ala + H2O
2-aminobenzoyl-Ser-Arg-Arg-Leu-Leu + Arg-Ala-Leu-Glu-(3-nitro)Tyr-Ala
-
Substrates: cleaves between Leu and Arg
Products: -
Products: -
?
2-aminobenzoyl-SSGSRRLLSEESY(NO2)-Ala + H2O
?
-
Substrates: cleaves between Leu and Ser
Products: -
Products: -
?
2-aminobenzoyl-Val-Phe-Arg-Ser-Leu-Lys-Tyr-Ala-Glu-Ser-Asp-(3-nitro)Tyr-Ala + H2O
2-aminobenzoyl-Val-Phe-Arg-Ser-Leu-Lys + Tyr-Ala-Glu-Ser-Asp-(3-nitro)Tyr-Ala
-
Substrates: cleaves between Lys and Tyr
Products: -
Products: -
?
Abz-Asp-Ile-Tyr-Ile-Ser-Arg-Arg-Leu-Leu-Gly-Thr-Phe-Thr-(3-nitro)Tyr-Ala-CONH2 + H2O
Abz-Asp-Ile-Tyr-Ile-Ser-Arg-Arg-Leu-Leu + Gly-Thr-Phe-Thr-(3-nitro)Tyr-Ala-CONH2
-
Substrates: i.e. QPC251-263
Products: -
Products: -
?
Abz-Asp-Ile-Tyr-Ile-Ser-Arg-Arg-Leu-Leu-Gly-Thr-Phe-Thr-(3-nitro)Tyr-Ala-NH2 + H2O
?
-
Substrates: favored quenched fluorogenic substrate
Products: -
Products: -
?
Abz-DIYISRRLL-GTFT-Tyx-A + H2O
Abz-DIYISRRLL + GTFT-Tyx-A
-
Substrates: -
Products: -
Products: -
?
Abz-DIYISRRLLGTFTY(NO2)A + H2O
?
-
Substrates: S1P displays pronounced positive cooperativity with this substrate derived from the viral coat glycoprotein of the lassa virus
Products: -
Products: -
?
Ac-AISRRLL-7-amido-4-methylcoumarin + H2O
Ac-AISRRLL + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Ac-FISRRLL-7-amido-4-methylcoumarin + H2O
Ac-FISRRLL + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Ac-IAVGRTLK-7-amido-4-methylcoumarin + H2O
Ac-IAVGRTLK + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Ac-IYISRRLL-7-amido-4-methylcoumarin + H2O
Ac-IYISRRLL + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Ac-QKSIAVGRTLK-7-amido-4-methylcoumarin + H2O
Ac-QKSIAVGRTLK + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Ac-RKLL-7-amido-4-methylcoumarin + H2O
Ac-RKLL + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Ac-RRLL-7-amido-4-methylcoumarin + H2O
Ac-RRLL + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Ac-RRLQ-7-amido-4-methylcoumarin + H2O
Ac-RRLQ + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Ac-RTLK-7-amido-4-methylcoumarin + H2O
Ac-RTLK + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Ac-SFITRRLQ-7-amido-4-methylcoumarin + H2O
Ac-SFITRRLQ + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Ac-YISRRLL-7-amido-4-methylcoumarin + H2O
Ac-YISRRLL + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Ac-YSSVSRKLL-7-amido-4-methylcoumarin + H2O
Ac-YSSVSRKLL + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
ATF6 precursor + H2O
nuclear ATF6
-
Substrates: rSt-1 and rSt-2 seem to affect the processing of ATF6 by SKI-1
Products: -
Products: -
?
brain-derived neurotrophic factor precursor + H2O
?
-
Substrates: cleaves at an RGLTLS site between Thr and Ser
Products: -
Products: -
?
CREB4 + H2O
?
-
Substrates: i.e. androgen-induced leucine zipper protein, C-terminal domain of CREB4 somehow confers resistance to cleavage by S1P, which can be released either by removal of the region or physiologically by some regulatory signal
Products: -
Products: -
?
Crimean Congo hemorrhagic fever virus glycoprotein + H2O
glycoprotein precursor Gn + glycoprotein precursor Gc
-
Substrates: -
Products: -
Products: -
?
Dabcyl-Arg-His-Ser-Ser-Arg-Arg-Leu-Leu-Arg-Ala-Leu-Glu-Gly-Gly-Lys(tetramethylrhodamine)-OH + H2O
?
Substrates: -
Products: -
Products: -
?
Dabcyl-Ser-Gly-Ser-Gly-Arg-Ser-Val-Leu-Ser-Phe-Glu-Ser-Gly-Ser-Lys(tetramethylrhodamine)-Arg-OH + H2O
?
Substrates: -
Products: -
Products: -
?
glycoprotein + H2O
?
-
Substrates: S1P is involved in the processing of the glycoproteins of the genetically more-distant South American hemorrhagic fever viruses Guanarito, Machupo, and Junin
Products: -
Products: -
?
Lassa virus envelope glycoprotein precursor + H2O
?
Substrates: the enzyme recognition motif RRLL is critical for the processing of the Lassa virus envelope glycoprotein in the endoplasmic reticulum/cis-Golgi compartment
Products: -
Products: -
?
Lassa virus glycoprotein + H2O
?
-
Substrates: cleavage at RRLL-sites
Products: -
Products: -
?
Lassa virus glycoprotein precursor GP-C + H2O
Lassa virus glycoprotein GP-2 + ?
-
Substrates: cleavage at the C-terminal end of the recognition motif R-R-L-L
Products: -
Products: -
?
Lassa virus glycoprotein precursor protein + H2O
peripheral virion attachment protein GP1 + fusion-active transmembrane protein GP2
-
Substrates: -
Products: Arg-Arg-Leu-Leu + Gly-Thr-Phe
Products: Arg-Arg-Leu-Leu + Gly-Thr-Phe
?
lymphocytic choriomeningitis virus glycoprotein precursor protein + H2O
peripheral virion attachment protein GP1 + fusion-active transmembrane protein GP2
-
Substrates: -
Products: Arg-Arg-Leu-Ala + Gly-Thr-Phe
Products: Arg-Arg-Leu-Ala + Gly-Thr-Phe
?
SREBP1 + H2O
?
-
Substrates: the enzyme mediates the cleavage and activation of SREBP1
Products: -
Products: -
?
sterol regulatory element-binding protein 1c + H2O
?
-
Substrates: -
Products: -
Products: -
?
sterol regulatory element-binding protein SREBP-2 + H2O
?
-
Substrates: -
Products: -
Products: -
?
succinyl-YISRRLL-7-amido-4-methylcoumarin + H2O
succinyl-YISRRLL + 7-amino-4-methylcoumarin
-
Substrates: -
Products: -
Products: -
?
(pro)renin receptor + H2O
soluble (pro)renin receptor + ?
-
Substrates: -
Products: -
Products: -
?
(pro)renin receptor + H2O
soluble (pro)renin receptor + ?
-
Substrates: -
Products: -
Products: -
?
arenavirus envelope glycoprotein precursor + H2O
?
Substrates: activation, F259A replacement at P7 of the viral protein substrate impaires the reaction, while replacement of with F does not affect enzyme processing. The catalytic pocket of the enzyme may interact with additional substrate residues distal from the actual cleavage site. Residue Y285 of the enzyme, located distal from the catalytic triad, is implicated in the molecular recognition of the aromatic signature residue at P7 and is crucial for efficient processing of OW and clade C NW arenavirus glycoprotein precursor
Products: -
Products: -
?
arenavirus envelope glycoprotein precursor + H2O
?
Substrates: activation/maturation
Products: -
Products: -
?
arenavirus envelope glycoprotein precursor + H2O
?
Substrates: -
Products: -
Products: -
?
ATF6 + H2O
?
-
Substrates: i.e. activating transcription factor 6
Products: -
Products: -
?
Crimean Congo hemorrhagic fever virus glycoprotein + H2O
?
-
Substrates: cleavage at RRLL-sites
Products: -
Products: -
?
Crimean Congo hemorrhagic fever virus glycoprotein + H2O
?
-
Substrates: posttranslational cleavage by furin/PC-mediated processing at its N-terminus at RSKR247 and by SKI-1 at its C-terminus at RRLL519
Products: -
Products: -
?
membrane-associated transcription factor bZIP28 + H2O
?
-
Substrates: endoplasmic reticulum stress-induced activation, the RRIL573 site, but not the RVLM373 site, on the lumen-facing domain of bZIP28 is critical for the biological function of bZIP28 under endoplasmic reticulum stress condition
Products: -
Products: -
?
membrane-associated transcription factor bZIP28 + H2O
?
-
Substrates: -
Products: -
Products: -
?
RsiW + H2O
?
-
Substrates: PrsW is both necessary and sufficient for site-1 cleavage of the anti-sigmaW factor RsiW. Site-2 cleavage depends on the prior action of PrsW
Products: -
Products: -
?
RsiW + H2O
?
-
Substrates: site-1 proteolysis of RsiW. Is converted to a C-terminally truncated form that remains membrane bound
Products: -
Products: -
?
RsiW + H2O
?
-
Substrates: PrsW is both necessary and sufficient for site-1 cleavage of the anti-sigmaW factor RsiW. Site-2 cleavage depends on the prior action of PrsW
Products: -
Products: -
?
sterol regulatory element-binding protein + H2O
?
-
Substrates: SREBP
Products: -
Products: -
?
sterol regulatory element-binding protein + H2O
?
-
Substrates: SREBP, cleaves the luminal loop following the tetrapeptide sequence Arg-Xaa-Xaa-Leu
Products: -
Products: -
?
sterol regulatory element-binding protein + H2O
?
-
Substrates: mutating the crucial Arg at position 486 to Ala blocks cleavage by dS1P
Products: -
Products: -
?
sterol regulatory element-binding protein + H2O
?
-
Substrates: S1P cleaves in the luminal loop of the membrane-bound SREBP precursor, cutting it in two. The NH2- and COOH-terminal domains remain membrane bound owing to their single membrane-spanning helices
Products: -
Products: -
?
sterol regulatory element-binding protein + H2O
?
-
Substrates: -
Products: -
Products: -
?
additional information
?
-
-
Substrates: initiates a process by which the transcriptionally active N-terminal fragments of SREBPs are released from membranes
Products: -
Products: -
?
additional information
?
-
-
Substrates: initiates a process by which the active fragments of the SREBPs translocate to the nucleus and activate genes controlling the synthesis and uptake of cholersterol and unsaturated fatty acids in animal cells
Products: -
Products: -
?
additional information
?
-
-
Substrates: peptides containing RSLK and RRLL are cleaved best
Products: -
Products: -
?
additional information
?
-
-
Substrates: RRLL peptide representing the Gn processing site is efficiently cleaves but an RKPL peptide representing the GC processing site is cleaved at negligible levels
Products: -
Products: -
?
additional information
?
-
-
Substrates: SKI-1 cleaves inactive proproteins at the motif R-X-(hydrophobic)-Z with Z being mostly Leu
Products: -
Products: -
?
additional information
?
-
Substrates: zymogen activation of the enzyme involving sequential autocatalytic processing of its N-terminal prodomain at sites B'/B followed by the C'/C sites. Enzyme autoprocessing results in intermediates whose catalytic domain remains associated with prodomain fragments of different lengths. All incompletely matured intermediates of SKI-1/S1P show full catalytic activity toward cellular substrates, whereas optimal cleavage of viral glycoproteins depends on B'/B processing. Incompletely matured forms of SKI-1/S1P further process cellular and viral substrates in distinct subcellular compartments
Products: -
Products: -
?
additional information
?
-
Substrates: the enzyme performs autocatalytic cleavage and activation. The cleavage of arenavirus glycoproteins, but not cellular substrates, critically depends on the autoprocessing of the enzyme, suggesting differences in the processing of cellular and viral substrates. The exogenous soluble enzyme is unable to process arenavirus lymphocytic choriomeningitis virus and pathogenic Lassa virus envelope glycoproteins displayed at the surface of enzyme-deficient cells, indicating that glycoprotein processing occurs in an intracellular compartment
Products: -
Products: -
?
additional information
?
-
Substrates: substrate specificity and activity of wild-type enzyme and pro-domain mutants towards cellular and viral substrates, construction and evaluation of a cell-based chimeric protein molecular sensor, containing the LASVGPC cleavage site IYISRRLL-/-G, to monitor endogenous enzyme activity, overview
Products: -
Products: -
?
additional information
?
-
Substrates: the SKI-1/S1P recognition site RRLL is present in the enzyme SKI-1/S1P prodomain and Lassa virus envelope glycoprotein precursor , but not in the lymphocytic choriomeningitis virus envelope glycoprotein precursor, it is crucial for the processing of the Lassa virus glycoprotein in the endoplasmic reticulum/cis-Golgi compartment
Products: -
Products: -
?
additional information
?
-
-
Substrates: caspase-11 directly associates with the enzyme and cleaves it at a specific site for activation. Generation of pro-enzyme exposes the N-terminal prodomain, which undergoes sequential autocatalytic processing in the endoplasmic reticulum at the RKVF133/RSLK137/ and RRAS166/RRLL186/ cleavage sites to generate the B-form (120 kDa) and C-form (106 kDa), respectively. The membrane-bound C-form is further cleaved at the shedding site (KHQKLL953/) to become the secreted form of the enzyme (98 kDa) in Golgi
Products: -
Products: -
-
additional information
?
-
-
Substrates: cleaves after lysine or leucine rather than arginine
Products: -
Products: -
?
additional information
?
-
-
Substrates: functions to control lipid biosynthesis and uptake in animal cells
Products: -
Products: -
?
additional information
?
-
-
Substrates: can cleave postsingle and possibly pairs of Thr residues in certain precursors
Products: -
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
(pro)renin receptor + H2O
soluble (pro)renin receptor + ?
-
Substrates: -
Products: -
Products: -
?
Ac-AISRRLL-7-amido-4-methylcoumarin + H2O
Ac-AISRRLL + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Ac-FISRRLL-7-amido-4-methylcoumarin + H2O
Ac-FISRRLL + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Ac-IAVGRTLK-7-amido-4-methylcoumarin + H2O
Ac-IAVGRTLK + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Ac-IYISRRLL-7-amido-4-methylcoumarin + H2O
Ac-IYISRRLL + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Ac-QKSIAVGRTLK-7-amido-4-methylcoumarin + H2O
Ac-QKSIAVGRTLK + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Ac-RKLL-7-amido-4-methylcoumarin + H2O
Ac-RKLL + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Ac-RRLL-7-amido-4-methylcoumarin + H2O
Ac-RRLL + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Ac-RRLQ-7-amido-4-methylcoumarin + H2O
Ac-RRLQ + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Ac-RTLK-7-amido-4-methylcoumarin + H2O
Ac-RTLK + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Ac-SFITRRLQ-7-amido-4-methylcoumarin + H2O
Ac-SFITRRLQ + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Ac-YISRRLL-7-amido-4-methylcoumarin + H2O
Ac-YISRRLL + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Ac-YSSVSRKLL-7-amido-4-methylcoumarin + H2O
Ac-YSSVSRKLL + 7-amino-4-methylcoumarin
Substrates: an arenavirus envelope glycoprotein precursor protein-derived peptide substrate
Products: -
Products: -
?
Lassa virus glycoprotein precursor protein + H2O
peripheral virion attachment protein GP1 + fusion-active transmembrane protein GP2
-
Substrates: -
Products: Arg-Arg-Leu-Leu + Gly-Thr-Phe
Products: Arg-Arg-Leu-Leu + Gly-Thr-Phe
?
lymphocytic choriomeningitis virus glycoprotein precursor protein + H2O
peripheral virion attachment protein GP1 + fusion-active transmembrane protein GP2
-
Substrates: -
Products: Arg-Arg-Leu-Ala + Gly-Thr-Phe
Products: Arg-Arg-Leu-Ala + Gly-Thr-Phe
?
membrane-associated transcription factor bZIP28 + H2O
?
-
Substrates: endoplasmic reticulum stress-induced activation, the RRIL573 site, but not the RVLM373 site, on the lumen-facing domain of bZIP28 is critical for the biological function of bZIP28 under endoplasmic reticulum stress condition
Products: -
Products: -
?
SREBP1 + H2O
?
-
Substrates: the enzyme mediates the cleavage and activation of SREBP1
Products: -
Products: -
?
succinyl-YISRRLL-7-amido-4-methylcoumarin + H2O
succinyl-YISRRLL + 7-amino-4-methylcoumarin
-
Substrates: -
Products: -
Products: -
?
arenavirus envelope glycoprotein precursor + H2O
?
Substrates: activation, F259A replacement at P7 of the viral protein substrate impaires the reaction, while replacement of with F does not affect enzyme processing. The catalytic pocket of the enzyme may interact with additional substrate residues distal from the actual cleavage site. Residue Y285 of the enzyme, located distal from the catalytic triad, is implicated in the molecular recognition of the aromatic signature residue at P7 and is crucial for efficient processing of OW and clade C NW arenavirus glycoprotein precursor
Products: -
Products: -
?
arenavirus envelope glycoprotein precursor + H2O
?
Substrates: activation/maturation
Products: -
Products: -
?
additional information
?
-
-
Substrates: initiates a process by which the active fragments of the SREBPs translocate to the nucleus and activate genes controlling the synthesis and uptake of cholersterol and unsaturated fatty acids in animal cells
Products: -
Products: -
?
additional information
?
-
Substrates: zymogen activation of the enzyme involving sequential autocatalytic processing of its N-terminal prodomain at sites B'/B followed by the C'/C sites. Enzyme autoprocessing results in intermediates whose catalytic domain remains associated with prodomain fragments of different lengths. All incompletely matured intermediates of SKI-1/S1P show full catalytic activity toward cellular substrates, whereas optimal cleavage of viral glycoproteins depends on B'/B processing. Incompletely matured forms of SKI-1/S1P further process cellular and viral substrates in distinct subcellular compartments
Products: -
Products: -
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additional information
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Substrates: the enzyme performs autocatalytic cleavage and activation. The cleavage of arenavirus glycoproteins, but not cellular substrates, critically depends on the autoprocessing of the enzyme, suggesting differences in the processing of cellular and viral substrates. The exogenous soluble enzyme is unable to process arenavirus lymphocytic choriomeningitis virus and pathogenic Lassa virus envelope glycoproteins displayed at the surface of enzyme-deficient cells, indicating that glycoprotein processing occurs in an intracellular compartment
Products: -
Products: -
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
CaCl2
-
recombinant S1P-1 activity can be stimulated by Ca2+, but is not dependent on Ca2+. Increases activity of recombinant S1P-1 60% at 4 mM, higher concentrations of CaCl2 lowers the activity
KCl
-
increases activity of recombinant S1P-1 25% dependent on the substrate used
NaCl
-
increases activity of recombinant S1P-1 25% at 50 mM dependent on the substrate used
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(2R,2'R)-2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino[(2S)-1-oxo-4-phenylbutane-2,1-diyl]imino]]bis(3-phenylpropanoic acid)
-
-
(2S,2'S)-2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino]]bis(3-methylbutanoic acid)
-
-
(2S,2'S)-2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino]]bis(4-phenylbutanoic acid)
-
-
(3S,4S,5S,6R)-2-([(2R,3S,4S,5S,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-methoxytetrahydro-2H-pyran-4-yl]amino)-6-(hydroxymethyl)tetrahydro-2H-thiopyran-3,4,5-triol
-
i.e. BJ-12-26-1, greatly reduces SKI-1 zymogen processing, and abolishes the processing of substrate SREBP-2
(3S,4S,5S,6R)-2-([(2S,3S,4R,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3-yl]amino)-6-(hydroxymethyl)tetrahydro-2H-thiopyran-3,4,5-triol
-
i.e. BJ-12-21-2, greatly reduces SKI-1 zymogen processing, and abolishes the processing of substrate SREBP-2
(R)-4-((diethylamino)methyl)-N-(2-methoxyphenethyl)-N-(pyrrolidin-3-yl)benzamide
inhibits endogenous SREBP processing in Chinese hamster ovary cells. Compound down-regulates the signal from an SRE-luciferase reporter gene in human embryonic kidney 293 cells and the expression of endogenous SREBP target genes in cultured HepG2 cells. In mice treated with the compound for 24 h, the expression of hepatic SREBP target genes is suppressed, and the hepatic rates of cholesterol and fatty acid synthesis are reduced
(S)-4-((diethylamino)methyl)-N-(2-methoxyphenethyl)-N-(pyrrolidin-3-yl)benzamide
purified S-enantiomer
1-(4-[[2-(2-methoxyphenyl)ethyl](pyrrolidin-3-yl)carbamoyl]benzyl)piperidine-3-carboxamide
-
-
2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino]]diacetic acid
-
-
3,4-dichloroisocoumarin
-
potent slow binding inhibitor, 100% inhibition by 0.05 mM
4-(2-azabicyclo[2.2.1]hept-2-ylmethyl)-N-[2-(2-methoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
-
-
4-(6-azabicyclo[3.2.1]oct-6-ylmethyl)-N-[2-(2-methoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
-
-
4-([[(1S,2S)-2-hydroxycyclohexyl]amino]methyl)-N-[2-(2-methoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
-
-
4-[(diethylamino)methyl]-N-[2-(2-ethoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
-
-
4-[(diethylamino)methyl]-N-[2-(2-methoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
-
-
4-[(diethylamino)methyl]-N-[2-(2-methoxyphenyl)ethyl]-N-[(3R)-pyrrolidin-3-yl]benzamide
-
-
4-[(diethylamino)methyl]-N-[2-(2-methylphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
-
-
4-[[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]methyl]-N-[2-(2-methoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
-
-
benzyl N-[(2-[(E)-[2-(2-oxo-2-[[(1S)-2-oxo-2-phenoxy-1-phenylethyl]amino]ethoxy)phenyl]diazenyl]phenoxy)acetyl]-L-phenylalaninate
-
competitive. E-isomer is thermally stable
benzyl N-[(2-[(E)-[2-(2-[[(2S)-3-methyl-1-oxo-1-phenoxybutan-2-yl]amino]-2-oxoethoxy)phenyl]diazenyl]phenoxy)acetyl]-L-leucinate
-
competitive. E-isomer is thermally stable
decanoyl-RRLL-chloromethylketone
the selective and cell-permeable small-peptide inhibitor inhibits the enzyme and leads to suppression of proliferation and metabolic activity of melanoma cells in vitro. The inhibitor induces classical apoptosis of melanoma cells in vitro and affects expression of several SKI-1 target genes including activating transcription factor 6. The compound induces cell death in an ATF6-independent manner
dibenzyl (2R,2'S)-2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino]]bis(3-methylbutanoate)
-
-
dibenzyl (2R,2'S)-2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino]]bis(3-phenylpropanoate)
-
-
N-[(2-[(E)-[2-(2-[[(1S)-1-carboxy-2-methylpropyl]amino]-2-oxoethoxy)phenyl]diazenyl]phenoxy)acetyl]-L-leucine
-
competitive. E-isomer is thermally stable
N-[2-(2,6-dichlorophenyl)ethyl]-4-[(diethylamino)methyl]-N-pyrrolidin-3-ylbenzamide
-
-
N-[2-(2-chlorophenyl)ethyl]-4-[(diethylamino)methyl]-N-pyrrolidin-3-ylbenzamide
-
-
N-[2-(2-chlorophenyl)ethyl]-4-[[3-(2-methylphenyl)piperidin-1-yl]methyl]-N-pyrrolidin-3-ylbenzamide
-
-
N-[2-(2-methoxyphenyl)ethyl]-4-(piperidin-1-ylmethyl)-N-pyrrolidin-3-ylbenzamide
-
-
N-[2-(2-methoxyphenyl)ethyl]-4-[[3-(2-methylphenyl)piperidin-1-yl]methyl]-N-pyrrolidin-3-ylbenzamide
-
-
N-[2-(4-chlorophenyl)ethyl]-4-[(diethylamino)methyl]-N-pyrrolidin-3-ylbenzamide
-
-
4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride
-
inhibits SKI-1 and the autocatalytic generation of St-1
PF-429242
-
potent S1P inhibitor both in vitro and in cell-based assays, PF-429242 inhibits S1P-mediated processing of arenavirus arenavirus glycoprotein precursor protein
PF429242
-
inhibotor suppresses the formation of soluble (pro)renin receptor
additional information
-
decanoyl-RVKR-chloromethylketone does not affect SKI-1-mediated processing; decanoyl-RVKR-chloromethylketone inhibition is selective to furin/PCs and does not affect SKI-1-mediated processing
-
additional information
-
SKI-1/S1P inhibition by overexpression of proSKI variants, results in reduced cholesterol synthesis and mRNA levels of the rate-limiting enzymes HMG-CoA reductase and squalene epoxidase in the cholesterol synthetic pathway. Inhibitory effect is maintained in the presence of homocysteine-induced endoplasmic reticulum stress. SKI-1/S1P inhibition also affects glycolysis and citric acid cycle
-
additional information
-
(Z-LL)2-chloromethylketone and PN1 have no effect on St-2 production. Overexpressed rSt-1 or rSt-2 impede ATF6 processing by SKI-1
-
additional information
-
not inhibited by Mn2+, 7B2 C-terminal peptide, ProSAAS235-244 peptide, ProSAAS235-246 peptide, trypsin inhibitor from bovine pancreas, trypsin inhibitor from soybean, Pefabloc SC (4-(2-aminoethyl) benzene sulphonyl fluoride), benzamidine, p-aminobenzamidine and chymostatin
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
cellular stress induced by tunicamycin does not regulate the production of St-2
-
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Alkalosis
Alkalosis monitored by 31P NMR in a human glioma cell line exposed to the anti-tumor drug 1,3-bis(2-chloroethyl)-1-nitrosourea.
Carcinogenesis
Inhibition of the Prohormone Convertase Subtilisin-Kexin Isoenzyme-1 Induces Apoptosis in Human Melanoma Cells.
Carcinoma
SREBP1 site 1 protease inhibitor PF-429242 suppresses renal cell carcinoma cell growth.
Carcinoma, Hepatocellular
Baicalin promoted site-2 protease and not site-1 protease in endoplasmic reticulum stress-induced apoptosis of human hepatocellular carcinoma cells.
Carcinoma, Hepatocellular
Human subtilase SKI-1/S1P is a master regulator of the HCV Lifecycle and a potential host cell target for developing indirect-acting antiviral agents.
Carcinoma, Hepatocellular
Human Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P) regulates cytoplasmic lipid droplet abundance: A potential target for indirect-acting anti-dengue virus agents.
Carcinoma, Renal Cell
SREBP1 site 1 protease inhibitor PF-429242 suppresses renal cell carcinoma cell growth.
Choriocarcinoma
The (pro)renin receptor and soluble (pro)renin receptor in choriocarcinoma.
Congenital Abnormalities
Patient with an autosomal-recessive MBTPS1-linked phenotype and clinical features of Silver-Russell syndrome.
Dengue
Suppressive Effects of the Site 1 Protease (S1P) Inhibitor, PF-429242, on Dengue Virus Propagation.
Fatty Liver
Human subtilase SKI-1/S1P is a master regulator of the HCV Lifecycle and a potential host cell target for developing indirect-acting antiviral agents.
Glioma
Alkalosis monitored by 31P NMR in a human glioma cell line exposed to the anti-tumor drug 1,3-bis(2-chloroethyl)-1-nitrosourea.
Glioma
Altered cytotoxicity of (2-chloroethyl)-3-sarcosinamide-1-nitrosourea in human glioma cell lines SK-MG-1 and SKI-1 correlates with differential transport kinetics.
Glioma
Characterization of the catecholamine extraneuronal uptake2 carrier in human glioma cell lines SK-MG-1 and SKI-1 in relation to (2-chloroethyl)-3-sarcosinamide-1-nitrosourea (SarCNU) selective cytotoxicity.
Glioma
Identification of a 116 kDa protein able to bind 1,3-bis(2-chloroethyl)-1-nitrosourea-damaged DNA as poly(ADP-ribose) polymerase.
Glioma
Mechanisms of resistance to (2-chloroethyl)-3-sarcosinamide-1-nitrosourea (SarCNU) in sensitive and resistant human glioma cells.
Hemorrhagic Fever, American
Site 1 protease is required for proteolytic processing of the glycoproteins of the South American hemorrhagic fever viruses Junin, Machupo, and Guanarito.
Hemorrhagic Fever, Crimean
Crimean-congo hemorrhagic fever virus glycoprotein precursor is cleaved by Furin-like and SKI-1 proteases to generate a novel 38-kilodalton glycoprotein.
Hemorrhagic Fever, Crimean
Crimean-Congo hemorrhagic fever virus glycoprotein processing by the endoprotease SKI-1/S1P is critical for virus infectivity.
Hemorrhagic Fever, Crimean
Crimean-Congo hemorrhagic fever virus glycoprotein proteolytic processing by subtilase SKI-1.
Hepatitis C
SKI-1/S1P inhibition: a promising surrogate to statins to block hepatitis C virus replication.
Infections
Human subtilase SKI-1/S1P is a master regulator of the HCV Lifecycle and a potential host cell target for developing indirect-acting antiviral agents.
Infections
Human Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P) regulates cytoplasmic lipid droplet abundance: A potential target for indirect-acting anti-dengue virus agents.
Infections
Novel circular, cyclic and acyclic ?(CH(2)O) containing peptide inhibitors of SKI-1/S1P: synthesis, kinetic and biochemical evaluations.
Infections
Targeting the proteolytic processing of the viral glycoprotein precursor is a promising novel anti-viral strategy against arenaviruses.
Infections
Therapeutic effect of post-exposure treatment with antiserum on severe fever with thrombocytopenia syndrome (SFTS) in a mouse model of SFTS virus infection.
Lymphocytic Choriomeningitis
Endoproteolytic processing of the lymphocytic choriomeningitis virus glycoprotein by the subtilase SKI-1/S1P.
Lymphocytic Choriomeningitis
Molecular characterization of the processing of arenavirus envelope glycoprotein precursors by subtilisin kexin isozyme-1/site-1 protease.
Lymphocytic Choriomeningitis
The role of proteolytic processing and the stable signal peptide in expression of the Old World arenavirus envelope glycoprotein ectodomain.
Lymphocytic Choriomeningitis
Tropism of CPMV to Professional Antigen Presenting Cells Enables a Platform to Eliminate Chronic Infections.
Melanoma
Inhibition of the Prohormone Convertase Subtilisin-Kexin Isoenzyme-1 Induces Apoptosis in Human Melanoma Cells.
Neoplasm Metastasis
Inhibition of the Prohormone Convertase Subtilisin-Kexin Isoenzyme-1 Induces Apoptosis in Human Melanoma Cells.
Neoplasms
Inhibition of the Prohormone Convertase Subtilisin-Kexin Isoenzyme-1 Induces Apoptosis in Human Melanoma Cells.
Neoplasms
SRC promotes survival and invasion of lung cancers with epidermal growth factor receptor abnormalities and is a potential candidate for molecular-targeted therapy.
Non-alcoholic Fatty Liver Disease
Regulation of SREBP-2 intracellular trafficking improves impaired autophagic flux and alleviates endoplasmic reticulum stress in NAFLD.
Prostatic Neoplasms
Nelfinavir inhibits regulated intramembrane proteolysis of sterol regulatory element binding protein-1 and activating transcription factor 6 in castration-resistant prostate cancer.
Severe Fever with Thrombocytopenia Syndrome
The cholesterol, fatty acid and triglyceride synthesis pathways regulated by site 1 protease (S1P) are required for efficient replication of severe fever with thrombocytopenia syndrome virus.
Silver-Russell Syndrome
Patient with an autosomal-recessive MBTPS1-linked phenotype and clinical features of Silver-Russell syndrome.
site-1 protease deficiency
Site-1 protease deficiency causes human skeletal dysplasia due to defective inter-organelle protein trafficking.
Thrombocytopenia
The cholesterol, fatty acid and triglyceride synthesis pathways regulated by site 1 protease (S1P) are required for efficient replication of severe fever with thrombocytopenia syndrome virus.
Vaccinia
Prosomatostatin is proteolytically processed at the amino terminal segment by subtilase SKI-1.
Virus Diseases
C(2)-Symmetric azobenzene-amino acid conjugates and their inhibition of Subtilisin Kexin Isozyme-1.
Virus Diseases
Hypomorphic mutation in the site-1 protease mbtps1 endows resistance to persistent viral infection in a cell-specific manner.
Virus Diseases
Tropism of CPMV to Professional Antigen Presenting Cells Enables a Platform to Eliminate Chronic Infections.
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.028
2-aminobenzoyl-Arg-Asn-Thr-Pro-Arg-Arg-Glu-Arg-Arg-Arg-Lys-Lys-Arg-Gly-Leu-(3-nitro)Tyr-Ala
-
pH 7.4, 37°C
0.02
2-aminobenzoyl-Arg-His-Ser-Ser-Arg-Arg-Leu-Leu-Arg-Ala-Ile-(3-nitro)Tyr-Ala
-
pH 7.4, 37°C
0.00096
2-aminobenzoyl-Arg-Ser-Leu-Lys-Tyr-Ala-Glu-Ser-Asp-(3-nitro)Tyr-Ala
-
pH 7.4, 37°C
0.0044
2-aminobenzoyl-Asp-Ile-Tyr-Ile-Ser-Arg-Arg-Leu-Leu-Gly-Thr-Phe-Thr-(3-nitro)Tyr-Ala
-
pH 7.4, 37°C
0.023
2-aminobenzoyl-Ser-Arg-Arg-Leu-Leu-Arg-Ala-Leu-Glu-(3-nitro)Tyr-Ala
-
pH 7.4, 37°C
0.00428
2-aminobenzoyl-Val-Phe-Arg-Ser-Leu-Lys-Tyr-Ala-Glu-Ser-Asp-(3-nitro)Tyr-Ala
-
pH 7.4, 37°C
0.0504
Ac-AISRRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.067
Ac-AISRRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0123
Ac-FISRRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.015
Ac-FISRRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0226
Ac-IAVGRTLK-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.0846
Ac-IAVGRTLK-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0047
Ac-IYISRRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.0074
Ac-IYISRRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0025
Ac-QKSIAVGRTLK-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.0156
Ac-QKSIAVGRTLK-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0274
Ac-RKLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.0564
Ac-RKLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0153
Ac-RRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.0228
Ac-RRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0971
Ac-RRLQ-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.2263
Ac-RRLQ-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0967
Ac-RTLK-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.2167
Ac-RTLK-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0443
Ac-SFITRRLQ-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.0784
Ac-SFITRRLQ-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0028
Ac-YISRRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.005
Ac-YISRRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.0056
Ac-YISRRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0057
Ac-YISRRLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
0.0212
Ac-YSSVSRKLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant wild-type enzyme
0.0281
Ac-YSSVSRKLL-7-amido-4-methylcoumarin
pH and temperature not specified in the publication, recombinant mutant Y285A
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.14
(2R,2'R)-2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino[(2S)-1-oxo-4-phenylbutane-2,1-diyl]imino]]bis(3-phenylpropanoic acid)
-
in 25 mM Tris, 25 mM MES, 2 mM CaCl2, pH 7.4, at 37°C
0.075
(2S,2'S)-2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino]]bis(3-methylbutanoic acid)
-
in 25 mM Tris, 25 mM MES, 2 mM CaCl2, pH 7.4, at 37°C
0.225
(2S,2'S)-2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino]]bis(4-phenylbutanoic acid)
-
in 25 mM Tris, 25 mM MES, 2 mM CaCl2, pH 7.4, at 37°C
0.265
2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino]]diacetic acid
-
in 25 mM Tris, 25 mM MES, 2 mM CaCl2, pH 7.4, at 37°C
231
4-(2-aminoethyl benzene)sulfonyl fluoride
-
substrate Abz-DIYISRRLL-GTFT-Tyx-A, 37°C, pH 7.4
57.7
Ac-VFRSLK-4-(2-aminoethyl benzene)sulfonyl fluoride
-
substrate Abz-DIYISRRLL-GTFT-Tyx-A, 37°C, pH 7.4
0.0118
benzyl N-[(2-[(E)-[2-(2-oxo-2-[[(1S)-2-oxo-2-phenoxy-1-phenylethyl]amino]ethoxy)phenyl]diazenyl]phenoxy)acetyl]-L-phenylalaninate
-
pH 7.4, 37°C
0.125
benzyl N-[(2-[(E)-[2-(2-[[(2S)-3-methyl-1-oxo-1-phenoxybutan-2-yl]amino]-2-oxoethoxy)phenyl]diazenyl]phenoxy)acetyl]-L-leucinate
-
pH 7.4, 37°C
0.125
dibenzyl (2R,2'S)-2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino]]bis(3-methylbutanoate)
-
in 25 mM Tris, 25 mM MES, 2 mM CaCl2, pH 7.4, at 37°C
0.0118
dibenzyl (2R,2'S)-2,2'-[(E)-diazene-1,2-diylbis[benzene-2,1-diyloxy(1-oxoethane-2,1-diyl)imino]]bis(3-phenylpropanoate)
-
in 25 mM Tris, 25 mM MES, 2 mM CaCl2, pH 7.4, at 37°C
0.0758
N-[(2-[(E)-[2-(2-[[(1S)-1-carboxy-2-methylpropyl]amino]-2-oxoethoxy)phenyl]diazenyl]phenoxy)acetyl]-L-leucine
-
pH 7.4, 37°C
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000175 - 0.0005
(R)-4-((diethylamino)methyl)-N-(2-methoxyphenethyl)-N-(pyrrolidin-3-yl)benzamide
0.000393 - 0.000971
(S)-4-((diethylamino)methyl)-N-(2-methoxyphenethyl)-N-(pyrrolidin-3-yl)benzamide
0.00016
1-(4-[[2-(2-methoxyphenyl)ethyl](pyrrolidin-3-yl)carbamoyl]benzyl)piperidine-3-carboxamide
Homo sapiens
-
-
0.000095
4-(2-azabicyclo[2.2.1]hept-2-ylmethyl)-N-[2-(2-methoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.000029
4-(6-azabicyclo[3.2.1]oct-6-ylmethyl)-N-[2-(2-methoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.00059
4-(benzyloxy)-N-[2-(2-chlorophenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.00031
4-(benzyloxy)-N-[2-(2-methoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.00051
4-(benzyloxy)-N-[2-(3-chlorophenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.0001
4-([[(1S 2S)-2-hydroxycyclohexyl]amino]methyl)-N-[2-(2-methoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.016
4-[(diethylamino)methyl]-N-[2-(2-ethoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.00054
4-[(diethylamino)methyl]-N-[2-(2-methoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.00017
4-[(diethylamino)methyl]-N-[2-(2-methoxyphenyl)ethyl]-N-[(3R)-pyrrolidin-3-yl]benzamide
Homo sapiens
-
-
0.0016
4-[(diethylamino)methyl]-N-[2-(2-methylphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.00014
4-[[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]methyl]-N-[2-(2-methoxyphenyl)ethyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.00043
N-[2-(2 6-dichlorophenyl)ethyl]-4-[(diethylamino)methyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.0014
N-[2-(2-chlorophenyl)ethyl]-4-(1-methylethoxy)-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.00084
N-[2-(2-chlorophenyl)ethyl]-4-[(diethylamino)methyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.000008
N-[2-(2-chlorophenyl)ethyl]-4-[[3-(2-methylphenyl)piperidin-1-yl]methyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
most potent inhibitor
0.009
N-[2-(2-fluorophenyl)ethyl]-4-(1-methylethoxy)-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.00025
N-[2-(2-methoxyphenyl)ethyl]-4-(piperidin-1-ylmethyl)-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.000037
N-[2-(2-methoxyphenyl)ethyl]-4-[[3-(2-methylphenyl)piperidin-1-yl]methyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.0096
N-[2-(3-chlorophenyl)ethyl]-4-(1-methylethoxy)-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.0037
N-[2-(4-chlorophenyl)ethyl]-4-[(diethylamino)methyl]-N-pyrrolidin-3-ylbenzamide
Homo sapiens
-
-
0.000175
(R)-4-((diethylamino)methyl)-N-(2-methoxyphenethyl)-N-(pyrrolidin-3-yl)benzamide
Homo sapiens
inhibitory profile is determined by measuring the luciferase activity of a transfected sterol regulatory element (SRE)-TATA-luciferase construct into HEK-293 cells
0.0005
(R)-4-((diethylamino)methyl)-N-(2-methoxyphenethyl)-N-(pyrrolidin-3-yl)benzamide
Homo sapiens
in HepG2 cells, compound inhibits cholesterol synthesis, with an IC50 of 0.0005 mM
0.000393
(S)-4-((diethylamino)methyl)-N-(2-methoxyphenethyl)-N-(pyrrolidin-3-yl)benzamide
Homo sapiens
inhibitory profile is determined by measuring the luciferase activity of a transfected sterol regulatory element (SRE)-TATA-luciferase construct into HEK-293 cells
0.000971
(S)-4-((diethylamino)methyl)-N-(2-methoxyphenethyl)-N-(pyrrolidin-3-yl)benzamide
Homo sapiens
purified S-enantiomer, inhibitory profile is determined by measuring the luciferase activity of a transfected sterol regulatory element (SRE)-TATA-luciferase construct into HEK-293 cells
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.007
-
first 997 amino acids of human S1P lacking the C-terminal transmembrane region prepared from Trichoplusia ni egg, High Five cells
0.022
-
first 997 amino acids of human S1P lacking the C-terminal transmembrane region prepared from Sf21 cells, 103fold purified
0.2
-
first 997 amino acids of human S1P lacking the C-terminal transmembrane region prepared from Sf21 cells
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
the enzyme SKI-1 is constitutively expressed in human pigment cells with higher SKI activity in seven out of eight melanoma cell lines compared with normal melanocytes, also detectable in tumor cells of melanoma metastases
brenda
-
osteosarcoma cell line used. Mineralizing UMR 106 cells express a 98 kDa active, soluble form of SKI-1 within biomineralization foci. Non-mineralizing UMR cells differentially process SKI-1 into smaller immunoreactive fragments
brenda
additional information
-
S1P is abundantly expressed in the chondrocytes in the developing wild-type forelimb at all stages
brenda
additional information
-
SW-13 cell, infected with crimean-Congo hemorrhagic fever virus
brenda
additional information
subtilisin-kexin isoenzyme-1 (SKI-1) expression and activity in human pigment cells in vitro, as well as in normal human skin and metastatic melanoma, overview
brenda
additional information
-
subtilisin-kexin isoenzyme-1 (SKI-1) expression and activity in human pigment cells in vitro, as well as in normal human skin and metastatic melanoma, overview
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
the truncated mutant DELTA AC SKI-1/S1P BTMD, truncated before the transmembrane domain, stays in the endoplasmic reticulum
-
brenda
-
relocalization of SP1 and SP2 with brefeldin A, reconstitution of the sequential cleavage of ATF6
brenda
-
cis-and medial-Golgi, but not in the trans-Golgi
brenda
-
SP1 localizes to the same compartment as SP2, the cis/medial Golgi
brenda
-
most of membrane-bound SKI-1 and its stumps St-1 and St-2 localize to the Golgi and can enter the endosomal/lysosomal compartments but do not sort to the cell surface
brenda
-
YpdC contains five transmembrane segments and two larger extracytoplasmic loops
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
malfunction
physiological function
additional information
malfunction
in CHO cells deficient of S1P (termed SRD-12B cells) glycoprotein GP-C processing is abrogated after Lassa virus infection
malfunction
-
postnatal ablation of site-1 protease results in chondrodysplasia and rapid growth plate disruption due to intracellular Col II entrapment concomitant with loss of chondrocyte hypertrophy. S1P ablation at E10.5 results in a complete loss of endochondral bone formation along with the presence of an enhanced cortical bone formation
malfunction
enzyme SKI-1 inhibition induces apoptosis of melanoma cells by a non-ATF6-dependent mechanism, overview
malfunction
soluble enzyme is unable to process arenavirus glycoproteinss at the cell surface
malfunction
-
enzyme ablation in the osterix-lineage in mice drastically reduces bone development and downregulates bone marrow-derived skeletal stem cells. These mice also suffer from spina bifida occulta with a characteristic lack of bone fusion in the posterior neural arches. Enzyme ablation results in an increased production of granulocytemacrophage progenitors
malfunction
-
enzyme gene disruption in mouse skeletal muscle reduces the transforming growth factor -beta1 target gene Mss51 expression and increases muscle mass and mitochondrial respiration
malfunction
-
enzyme inhibition inactivates ATF6 and SREBP2 in CFBE41o cells and significantly increases the gene expression of p.Phe508del-cystic fibrosis transmembrane conductance regulator
physiological function
-
site-1 protease has fundamental roles in the preservation of postnatal growth plate through chondrocyte differentiation and Col II deposition and functions to couple growth plate maturation to trabecular bone development in growing mice
physiological function
the enzyme regulates cartilage development, bone mineralization, and processing of viral glycoproteins, its overexpression is linked to carcinogenesis in some solid tumors, biological role of enzyme SKI-1 in melanoma development, overview
physiological function
the enzyme plays crucial roles in cellular homeostatic functions and is hijacked by pathogenic viruses for the processing of their envelope glycoproteins. Zymogen activation of the enzyme involves sequential autocatalytic processing of its N-terminal prodomain at sites B'/B followed by the C'/C sites. All incompletely matured intermediates of SKI-1/S1P showed full catalytic activity toward cellular substrates, whereas optimal cleavage of viral glycoproteins depended on B'/B processing. Incompletely matured forms of SKI-1/S1P further process cellular and viral substrates in distinct subcellular compartments
physiological function
the arenaviruses are an important family of emerging viruses that includes several causative agents of severe hemorrhagic fevers in humans that represent serious public health problems. A crucial step of the arenavirus life cycle is maturation of the envelope glycoprotein precursor by the cellular subtilisin kexin isozyme 1/site 1 protease
physiological function
a crucial step in the life cycle of arenaviruses is the biosynthesis of the mature fusion-active viral envelope glycoprotein that is essential for virus-host cell attachment and entry. The maturation of the arenavirus envelope glycoprotein precursor critically depends on proteolytic processing by the cellular proprotein convertase subtilisin kexin isozyme-1/site-1 protease
physiological function
-
the Arabidopsis membrane-associated transcription factor, bZIP28, is the functional equivalent of mammalian ATF6, which relocates from the endoplasmic reticulum to the Golgi where it is proteolytically processed by the enzyme and released from the membrane to the nucleus to mediate the unfolded protein response to either promote cell survival or programmed cell death depending on different developmental context or stress severity. The canonical site-1 protease cleavage site plays a pivotal role in activation and function of bZIP28 during unfolded protein response in plants
physiological function
-
S1P ablation in the osterix lineage results in osteochondrodysplasia and variable degrees of early postnatal scoliosis. Embryonically, Runx2 and osterix expression are normal, but S1P ablation results in a delay in vascular invasion and endochondral bone development. Mice appear normal when born, but by day 7 display pronounced dwarfism with fragile bones that exhibit significantly reduced mineral density, mineral apposition rate, bone formation rate and reduced osteoblasts. Mice suffer from a drastic reduction in bone marrow mesenchymal progenitors and a drastic reduction in hematopoietic lineage-negative, endothelial-negative, CD105+ skeletal stem cells. Bone marrow mesenchymal progenitors are unable to differentiate into osteoblasts in vitro, with no effect on adipogenic differentiation
physiological function
-
siRNA-mediated reduction of endogenous S1P in cChinese hamster ovary cells attenuates soluble (pro)renin receptor generation. Overexpression of S1P by transient transfection in this cell line increases s(P)RR generation. The S1P inhibitor PF429242 suppresses the generation of soluble (pro)renin receptor
physiological function
-
inhibition of S1P enzymatic activity in human hepatoma Huh-7.5.1 cells results in a robust reduction of the numbers of lipid droplets and lipid droplet-positive areas and effectively inhibits infection by dengue virsu DENV. Pre-treatment of Huh-7.5.1 cells with PF-429242 results in a dose-dependent inhibition of DENV and an about 3-log decrease in DENV-2 titer with 20 microM of PF-429242. Post-treatment of DENV-2 infected Huh-7.5.1 cells with PF-429242 does not affect viral RNA abundance, but it does compromise the assembly and/or release of infectious virus particles. PF-429242 antiviral activity is reversed by exogenous oleic acid
physiological function
-
inhibition of site-1 protease leads to a profound reduction in plasmablast number linked to induction of autophagy. Plasmablasts generated in the presence of site-1 protease inhibitor segregate into CD38high and CD38low populations, the latter characterized by a marked reduction in the capacity to secrete IgG. Site-1 protease inhibition is accompanied by a distinctive change in gene expression associated with amino acid, steroid and fatty acid synthesis pathways
physiological function
-
the enzyme plays a role in the lineage specification of hematopoietic stem cells and/or their progenitors for development of a normal hematopoietic niche. The enzyme is fundamentally required for maintaining a balanced regenerative capacity of the bone marrow niche
physiological function
-
the enzyme is a negative regulator of muscle mass and mitochondrial respiration
physiological function
-
enzyme-derived soluble (pro)renin receptor exerts a key role in determining renal type 2 receptor expression and, thus, urine concentrating capability
additional information
9 amino acid residues at the cleavage site (P1-P8) and P1' are necessary and sufficient to define the subcellular location of processing and to determine to what extent processing of a substrate depends on SKI-1/S1P maturation
additional information
modeling of the SKI-1/S1P catalytic pocket identifies Y285 as a residue that potentially interacts with arenavirus envelope glycoprotein precursor residue Y253. The the catalytic triad is formed by residues D218, H249, and S414
additional information
-
modeling of the SKI-1/S1P catalytic pocket identifies Y285 as a residue that potentially interacts with arenavirus envelope glycoprotein precursor residue Y253. The the catalytic triad is formed by residues D218, H249, and S414
additional information
the transmembrane anchorage and the cytoplasmic domain of SKI-1/S1P are dispensable for arenavirus glycoprotein processing
Show AA Sequence and Transmembrane Helices (1542 entries)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
35000
-
SDS-PAGE, predominant form in non-mineralizing cultures are smaller than 35 kDa
98000
98000
-
SDS-PAGE, expressed as a soluble enzyme in mineralizing UMR 106 cells
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
proteolytic modification
proteolytic modification
-
SP1-A is inactive and undergoes autocatalytic processing, generating an active form S1P-B, which is further cleaved after residue 186 to generate S1P-C
proteolytic modification
-
protein is inactive and undergoes autocatalytic processing, generating an active form S1P-B, which is further cleaved at an internal RRLL sequence to generate an active S1P-C
proteolytic modification
-
proSKI-1 is processed into two membrane-bound forms of SKI-1: 120000 Da and 106000 Da
proteolytic modification
zymogen activation of the enzyme involves sequential autocatalytic processing of its N-terminal prodomain at sites B'/B followed by the C'/C sites. Autocatalytic maturation by sequential cleavages of the N-terminal pro-domain first at sites B'/B (RKVF2RSLK1372), followed by site C (RRLL1862), with crucial roles for R and V/L residues at P4 and P2 (fourth and second residue upstream the scissile bond, respectively). Enzyme autoprocessing results in intermediates whose catalytic domain remains associated with prodomain fragments of different lengths. 9 Amino acid residues at the cleavage site (P1-P8) and P1' are necessary and sufficient to define the subcellular location of processing and to determine to what extent processing of a substrate depends on SKI-1/S1P maturation. Mature enzyme retains prodomain fragments of different lengths, overview. The post-translational modifications are crucial for the subcellular localization of autoprocessing intermediates of the enzyme
proteolytic modification
the enzyme performs autocatalytic cleavage and activation depending on the recognition site RRLL, present in the enzyme prodomain
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
E75A/E76A
-
is catalytically inactive and traps RsiW in a complex in which the anti-sigma factor is protected from undergoing proteolysis
E95K
-
missense mutant with a a dominant (gain-of-function) mutation. Exhibits heightened resistance to the SdpC toxin in cells lacking the SdpI immunity protein. Is locked in a state that causes constitutive activation of sigmaW
H175A
-
is catalytically inactive and traps RsiW in a complex in which the anti-sigma factor is protected from undergoing proteolysis
E75A/E76A
-
is catalytically inactive and traps RsiW in a complex in which the anti-sigma factor is protected from undergoing proteolysis
-
E95K
-
missense mutant with a a dominant (gain-of-function) mutation. Exhibits heightened resistance to the SdpC toxin in cells lacking the SdpI immunity protein. Is locked in a state that causes constitutive activation of sigmaW
-
H175A
-
is catalytically inactive and traps RsiW in a complex in which the anti-sigma factor is protected from undergoing proteolysis
-
H249A
P1003S
-
natural mutation identified in a female patient. The mutant protein is able to complement lipid and cholesterol biosynthetic capacities in cells that lack S1P and is abundant in both the ER and the Golgi
R130A/K131A
-
proSKI variant that exhibits no basic residue at the P4 position, has no effect on HMG-CoA reductase mRNA levels
R130E/R134E
site-directed mutagenesis, the double mutations at the B'/B site prevents autoprocessing
R134E
additional information
H249A
-
active site mutant, autocatalytic generation of St-1 is abrogated, St-2 fragment is generated at a level of ca. 15%
H249A
site-directed mutagenesis, catalytically inactive mutant showing no autoprocessing
R134E
-
proSKI variant that lacks autocatalytic primary cleavage site RSLK, most efficient inhibitor of HMG-CoA reductase expression
R134E
site-directed mutagenesis, the single prodomain mutant, at the B autoprocessing site, allows maturation comparably with the wild-type enzyme
additional information
-
prsW insertion/deletion mutant prsW::erm exacerbates the growth defect of an sdpI mutant
additional information
-
in a ypdC null mutant, induction of sigmaW-controlled genes is abolished and site-1 proteolysis of RsiW is completely blocked. Defect of sigmaW induction is complemented by ectopically integrated ypdC under xylose control in a heterologous Escherichia coli system
additional information
-
prsW insertion/deletion mutant prsW::erm exacerbates the growth defect of an sdpI mutant
-
additional information
-
S1P-deficient cells, ATF6 processing partially blocked
additional information
stable cell lines inducibly expressing S1P-adapted alpha1-antitrypsin variants inhibit the proteolytic maturation of glycoprotein GP-C. Introduction of the S1P recognition motifs RRIL and RRLL into the reactive center loop of alpha1-antitrypsin results in abrogation of glycoprotein GP-C processing by endogenous S1P to a similar level observed in S1P-deficient cells. Moreover, S1P-specific alpha1-antitrypsins significantly inhibit replication and spread of a replication-competent recombinant vesicular stomatitis virus expressing the Lassa virus glycoprotein GP as well as authentic Lassa virus
additional information
-
in the triple shedding site mutant KLL/A autocatalytic generation of St-1 is abrogated, St-2 fragment is generated at a level of ca. 15%
additional information
-
Crimean Congo hemorrhagic fever virus-infected cells deficient in SKI-1/S1P produce no infectious virus, although precursor Gn and precursor Gc accumulate normally in the Golgi apparatus, the site of virus assembly. Complementation of SKI-1/S1P-deficient cells with a SKI-1/S1P expression vector restores release of infectious virus
additional information
-
using SRD12B mutant cells lacking the S1P gene, it is shown that lack of glycoprotein processing of Junin virus dramatically reduces production of infectious virus and prevents cell-to-cell propagation. Infection of S1P-deficient cells results in viral persistence over several weeks without the emergence of escape variants able to use other cellular proteases for GP processing
additional information
the soluble form of the enzyme is truncated before the transmembrane domain and comprised the ectodomain, followed by a C-terminal V5 tag, i.e. DELTA AC SKI-1/S1P BTMD. Extended mutagenesis performed on a region proximal to the C site results in normal SKI-1/S1P maturation at the B'/B intermediate state, suggesting that processing at B'/B either precedes or occurs independently of C site cleavage. The combined mutation at the C and C' sites results in marked reduction of the mature C form indicating that, similar to B'/B, mutation of both C and C' processing sites is required to prevent maturation
additional information
-
complete silencing of SKI-1/SP1 results in an embryonic lethal phenotype, elimination of about 70-90% of SKI-1/SP1 protein expression in liver results in a drop of ca. 50% in the level of circulating cholesterol and triglycerides, cholesterol and fatty acid biosynthesis in hepatocytes declines by 75%, low density lipoprotein receptor mRNA declines by 50%
additional information
-
cartilage-specific S1P knockout mice, exhibit chondrodysplasia and a complete lack of endochondral ossification even though Runx2 expression, Indian hedgehog signaling, and osteoblastogenesis is intact. Substantial increase in chondrocyte apoptosis. Collagen network is disorganized and collagen becomes entrapped in chondrocytes. Endoplasmic reticulum in chondrocytes is engorged and fragmented in a manner characteristic of severe endoplasmic reticulum stress
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
first 997 amino acids of human S1P lacking the C-terminal transmembrane region 103fold purified by immobilised metal affinity chromatography on Co2+ column
-
recombinant C-terminally His6-tagged wild-type mutant enzyme from HEK-293T cell medium by immobilized metal affinity chromatography
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
cDNA encoding amino acids 17 to 997, encompassing the prodomain, catalytic domain, and cysteine-rich domain of soluble site 1 protease (sS1P) is expressed in CHO cells
first 997 amino acids of human S1P lacking the C-terminal transmembrane region. Full-length sequence of human S1P. Both tagged with a C-terminal 8 x His-tag, subcloned into the entry vector pDONR201 and expressed by baculovirus expression vector system in Sf9 cells. Additionally, first 997 amino acids of human S1P lacking the C-terminal transmembrane region expressed in Sf21 cells and Trichoplusia ni egg, High Five cells
-
full length SKI-1 and its H249A mutant expressed in HEK-293 cells, M19 cells, HuH7 cells and Hep-G2 cells. Wild-type SKI-1 and mutants H249A, L925A and K948A expressed in SRD-12B and CHO-K1 cells. Wild-type SKI-1 or a secretable form of St-1 containing a signal peptide followed by a FLAG tag at the N terminus and a V5 tag at the C terminus overexpressed in CHO-K1 cells. rSt-1 coexpressed with protease inhibitors in CHO-K1 and Neuro-2a cells. Mutants I985A, I989L, M990L, M990A, M990I, Y994A, N995A, and double mutant Y994A/N995A expressed in CHO-K1 cells
-
functional expression of full-length wild-type enzyme, which undergoes complete autoprocessing, in SRD12B cells. Recombinant expression HEK-293T and CHO cells, real-time quantitative PCR expression analysis
prsW+ and mutant E95K expressed in Escherichia coli. PrsW active-site mutants expressed in Bacillus subtilis
-
SKI-1/S1P deficient SRD12B cells transiently transfected with SKI-1/S1P-containing vector
-
transient expression of C-terminally His6-tagged full-length wild-type enzyme and a soluble enzyme variant truncated before the transmembrane domain, the catalytically inactive mutant H249A, B'/B, B' mutants of enzyme in HEK-293T cells, secretion of proteins. Wild-type and the DELTA AC SKI-1/S1P FL mutant are expressed in the SKI-I/S1P-deficient CHO cell line SRD12B, which lacks active endogenous enzyme
transient expression of wild-type and mutant enzymes in enzyme-deficient SRD12B cells
truncated from lacking the COOH-terminal membrane anchor, expressed in CHO cells
truncated from lacking the COOH-terminal membrane anchor, expressed in CHO cells
-
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
degradation
-
S1P reduces the size of the luminal domain to prepare ATF6 to be an optimal S2P substrate
medicine
additional information
medicine
-
S1P plays an integral role in skeletal development. S1P activity is necessary for a specialized endoplasmic reticulum stress response required by chondrocytes for the genesis of normal cartilage and thus endochondral ossification
medicine
-
useful role of SKI-1/S1P in controlling cholesterol synthesis, particularly in the presence of endoplasmic reticulum stress. SKI-1/S1P inhibition may be a potential tool for the treatment of alcohol-induced liver steatosis
medicine
-
SKI-1/S1P processing is strictly required for incorporation of viral glycoproteins. SKI-1/S1P may represent a promising antiviral target
medicine
small-molecule S1P inhibitors are capable of reducing cholesterol and fatty acid synthesis in vivo and, therefore, represent a potential new class of therapeutic agents for dyslipidemia and for a variety of cardiometabolic risk factors associated with diabetes, obesity, and the metabolic syndrome
medicine
glycoprotein cleavage by S1P is a promising target for the development of novel anti-arenaviral strategies
medicine
-
in fibroblasts of mucolipidosis type II mice and Niemann-Pick type C patients characterized by aberrant cholesterol accumulation, the proteolytic cleavage of the alpha/beta-subunit precursor of N -acetylglucosamine-1-phosphotransferase is not impaired
medicine
-
in fibroblasts of mucolipidosis type II mice and Niemann-Pick type C patients characterized by aberrant cholesterol accumulation, the proteolytic cleavage of the alpha/beta-subunit precursor of N -acetylglucosamine-1-phosphotransferase is not impaired
medicine
-
a female patient with a heterozygous missense mutation in the transmembrane domain of S1P (Pro1003Ser) displays episodic, activity-induced, focal myoedema and myalgias with hyperCKemia. The clinical phenotype includes gastrointestinal hypomotility, ocular migraines, and polycystic ovary syndrome. The mutation leads to increased activation of protein response and lipid and cholesterol regulatory pathways and localization of S1P Pro1003Ser in the Golgi
medicine
-
S1P is a potential target for indirect-acting pan-serotypic anti-dengue virus agents
additional information
-
cleaves glycoprotein, the only cleaved glycoprotein is incorporated into virions and this is necessary for the formation of infectious virus
additional information
-
S1P is required for the endoplasmic reticulum stress response as well as for lipid synthesis
additional information
-
PrsW is responsible for sensing antimicrobial peptides that damage the cell membrane and other agents that cause cell envelope stress
additional information
-
PrsW is responsible for sensing antimicrobial peptides that damage the cell membrane and other agents that cause cell envelope stress
-
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Seidah, N.G.; Benjannet, S.; Hamelin, J.; Mamarbachi, A.M.; Basak, A.; Marcinkiewicz, J.; Mbikay, M.; Chretien, M.; Marcinkiewicz, M.
The subtilisin/kexin family of precursor convertases. Emphasis on PC1, PC2/7B2, POMC and the novel enzyme SKI-1
Ann. N. Y. Acad. Sci.
885
57-74
1999
Rattus norvegicus
brenda
DeBose-Boyd, R.A.; Brown, M.S.; Li, W.P.; Nohturfft, A.; Goldstein, J.L.; Espenshade, P.J.
Transport-dependent proteolysis of SREBP: relocation of site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi
Cell
99
703-712
1999
Cricetulus griseus
brenda
Basak, A.; Chretien, M.; Seidah, N.G.
A rapid fluorometric assay for the proteolytic activity of SKI-1/S1P based on the surface glycoprotein of the hemorrhagic fever Lassa virus
FEBS Lett.
514
333-339
2002
Homo sapiens
brenda
Espenshade, P.J.; Cheng, D.; Goldstein, J.L.; Brown, M.S.
Autocatalytic processing of site-1 protease removes propeptide and permits cleavage of sterol regulatory element-binding proteins
J. Biol. Chem.
274
22795-22804
1999
Cricetulus griseus
brenda
Cheng, D.; Espenshade, P.J.; Slaughter, C.A.; Jaen, J.C.; Brown, M.S.; Goldstein, J.L.
Secreted site-1 protease cleaves peptides corresponding to luminal loop of sterol regulatory element-binding proteins
J. Biol. Chem.
274
22805-22812
1999
Mammalia
brenda
Toure, B.B.; Munzer, J.S.; Basak, A.; Benjannet, S.; Rochemont, J.; Lazure, C.; Chretien, M.; Seidah, N.G.
Biosynthesis and enzymatic characterization of human SKI-1/S1P and the processing of its inhibitory prosegment
J. Biol. Chem.
275
2349-2358
2000
Homo sapiens
brenda
Vincent, M.J.; Sanchez, A.J.; Erickson, B.R.; Basak, A.; Chretien, M.; Seidah, N.G.; Nichol, S.T.
Crimean-Congo hemorrhagic fever virus glycoprotein proteolytic processing by subtilase SKI-1
J. Virol.
77
8640-8649
2003
Homo sapiens
brenda
Seidah, N.G.; Mowla, S.J.; Hamelin, J.; Mamarbachi, A.M.; Benjannet, S.; Toure, B.B.; Basak, A.; Munzer, J.S.; Marcinkiewicz, J.; Zhong, M.; Barale, J.C.; Lazure, C.; Murphy, R.A.; Chretien, M.; Marcinkiewicz, M.
Mammalian subtilisin/kexin isozyme SKI-1: A widely expressed proprotein convertase with a unique cleavage specificity and cellular localization
Proc. Natl. Acad. Sci. USA
96
1321-1326
1999
Homo sapiens, Rattus norvegicus (Q9WTZ3)
brenda
Basak, S.; Stewart, N.A.; Chretien, M.; Basak, A.
Aminoethyl benzenesulfonyl fluoride and its hexapeptide (Ac-VFRSLK) conjugate are both in vitro inhibitors of subtilisin kexin isozyme-1
FEBS Lett.
573
186-194
2004
Homo sapiens
brenda
Shen, J.; Prywes, R.
Dependence of site-2 protease cleavage of ATF6 on prior site-1 protease digestion is determined by the size of the luminal domain of ATF6
J. Biol. Chem.
279
43046-43051
2004
Homo sapiens
brenda
Seidah, N.G.; Chretien, M.
Proprotein convertase SKI-1/SIP
Handbook of Proteolytic Enzymes (Barrett, A. J. , Rawlings, N. D. , Woessner, J. F. , Eds. ) Academic Press
2
1845-1847
2004
Cricetulus griseus, Arabidopsis thaliana, Homo sapiens, Mus musculus, Oryza sativa, Rattus norvegicus
-
brenda
Sanchez, A.J.; Vincent, M.J.; Erickson, B.R.; Nichol, S.T.
Crimean-congo hemorrhagic fever virus glycoprotein precursor is cleaved by Furin-like and SKI-1 proteases to generate a novel 38-kilodalton glycoprotein
J. Virol.
80
514-525
2006
Homo sapiens
brenda
Stirling, J.; OHare, P.
CREB4, a transmembrane bZip transcription factor and potential new substrate for regulation and cleavage by S1P
Mol. Biol. Cell
17
413-426
2005
Homo sapiens
brenda
Ye, J.; Rawson, R.B.; Komuro, R.; Chen, X.; Dave, U.P.; Prywes, R.; Brown, M.S.; Goldstein, J.L.
ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs
Mol. Cell
6
1355-1364
2000
Cricetulus griseus
brenda
Lenz, O.; Ter Meulen, J.; Klenk, H.D.; Seidah, N.G.; Garten, W.
The Lassa virus glycoprotein precursor GP-C is proteolytically processed by subtilase SKI-1/S1P
Proc. Natl. Acad. Sci. USA
98
12701-12702
2001
Homo sapiens
brenda
Hay, B.A.; Abrams, B.; Zumbrunn, A.Y.; Valentine, J.J.; Warren, L.C.; Petras, S.F.; Shelly, L.D.; Xia, A.; Varghese, A.H.; Hawkins, J.L.; Van Camp, J.A.; Robbins, M.D.; Landschulz, K.; Harwood, H.J.
Aminopyrrolidineamide inhibitors of site-1 protease
Bioorg. Med. Chem. Lett.
17
4411-4414
2007
Homo sapiens
brenda
De Windt, A.; Rai, M.; Bernier, L.; Thelen, K.; Soini, J.; Lefebvre, C.; Chintawar, S.; Lavigne, J.; Saarinen, L.; Kytoemaeki, L.; Munzer, J.S.; Luetjohann, D.; Pandolfo, M.; Davignon, J.; Seidah, N.G.; Laaksonen, R.
Gene Set Enrichment Analysis Reveals Several Globally Affected Pathways due to SKI-1/S1P Inhibition in HepG2 Cells
DNA Cell Biol.
26
765-772
2007
Homo sapiens
brenda
Ellermeier, C.D.; Losick, R.
Evidence for a novel protease governing regulated intramembrane proteolysis and resistance to antimicrobial peptides in Bacillus subtilis
Genes Dev.
20
1911-1922
2006
Bacillus subtilis, Bacillus subtilis PY79
brenda
Pullikotil, P.; Benjannet, S.; Mayne, J.; Seidah, N.G.
The proprotein convertase SKI-1/S1P: Alternate translation and subcellular localization
J. Biol. Chem.
282
27402-27413
2007
Homo sapiens
brenda
Patra, D.; Xing, X.; Davies, S.; Bryan, J.; Franz, C.; Hunziker, E.B.; Sandell, L.J.
Site-1 protease is essential for endochondral bone formation in mice
J. Cell Biol.
179
687-700
2007
Mus musculus
brenda
Bergeron, E.; Vincent, M.J.; Nichol, S.T.
Crimean-Congo hemorrhagic fever virus glycoprotein processing by the endoprotease SKI-1/S1P is critical for virus infectivity
J. Virol.
81
13271-13276
2007
Homo sapiens
brenda
Heinrich, J.; Wiegert, T.
YpdC determines site-1 degradation in regulated intramembrane proteolysis of the RsiW anti-sigma factor of Bacillus subtilis
Mol. Microbiol.
62
566-579
2006
Bacillus subtilis
brenda
Bodvard, K.; Mohlin, J.; Knecht, W.
Recombinant expression, purification, and kinetic and inhibitor characterisation of human site-1-protease
Protein Expr. Purif.
51
308-319
2007
Homo sapiens
brenda
Buraczewska, I.; Berne, B.; Lindberg, M.; Loden, M.; Toermae, H.
Long-term treatment with moisturizers affects the mRNA levels of genes involved in keratinocyte differentiation and desquamation
Arch. Dermatol. Res.
301
175-181
2009
Rattus norvegicus
brenda
Hawkins, J.L.; Robbins, M.D.; Warren, L.C.; Xia, D.; Petras, S.F.; Valentine, J.J.; Varghese, A.H.; Wang, I.K.; Subashi, T.A.; Shelly, L.D.; Hay, B.A.; Landschulz, K.T.; Geoghegan, K.F.; Harwood, H.J.
Pharmacologic inhibition of site 1 protease activity inhibits sterol regulatory element-binding protein processing and reduces lipogenic enzyme gene expression and lipid synthesis in cultured cells and experimental animals
J. Pharmacol. Exp. Ther.
326
801-808
2008
Homo sapiens (Q14703), Homo sapiens
brenda
Rojek, J.M.; Lee, A.M.; Nguyen, N.; Spiropoulou, C.F.; Kunz, S.
Site 1 protease is required for proteolytic processing of the glycoproteins of the South American hemorrhagic fever viruses Junin, Machupo, and Guanarito
J. Virol.
82
6045-6051
2008
Homo sapiens
brenda
Matthews, K.; Kunte, A.; Tambe-Ebot, E.; Rawson, R.
Alternative processing of sterol regulatory element binding protein during larval development in Drosophila melanogaster
Genetics
181
119-128
2009
Drosophila melanogaster
brenda
Yellaturu, C.; Deng, X.; Park, E.; Raghow, R.; Elam, M.
Insulin enhances the biogenesis of nuclear sterol regulatory element-binding protein (SREBP)-1c by posttranscriptionaldown-regulation of insig-2A and its dissociation from SREBP cleavage-activating protein (SCAP)SREBP-1c complex
J. Biol. Chem.
284
31726-31734
2009
Rattus norvegicus
brenda
Amarneh, B.; Matthews, K.A.; Rawson, R.B.
Activation of sterol regulatory element-binding protein by the caspase Drice in Drosophila larvae
J. Biol. Chem.
284
9674-9682
2009
Drosophila melanogaster
brenda
Maisa, A.; Stroeher, U.; Klenk, H.D.; Garten, W.; Strecker, T.
Inhibition of Lassa virus glycoprotein cleavage and multicycle replication by site 1 protease-adapted alpha(1)-antitrypsin variants
PLoS Negl. Trop. Dis.
3
e446
2009
Cricetulus griseus (Q9Z2A8)
brenda
Basak, A.; Mitra, D.; Das, A.K.; Mohottalage, D.; Basak, A.
C2-Symmetric azobenzene-amino acid conjugates and their inhibition of Subtilisin Kexin Isozyme-1
Bioorg. Med. Chem. Lett.
20
3977-3981
2010
Homo sapiens
brenda
Zandberg, W.F.; Benjannet, S.; Hamelin, J.; Pinto, B.M.; Seidah, N.G.
N-glycosylation controls trafficking, zymogen activation and substrate processing of proprotein convertases PC1/3 and subtilisin kexin isozyme-1
Glycobiology
21
1290-1300
2011
Homo sapiens
brenda
Patra, D.; DeLassus, E.; Hayashi, S.; Sandell, L.J.
Site-1 protease is essential to growth plate maintenance and is a critical regulator of chondrocyte hypertrophic differentiation in postnatal mice
J. Biol. Chem.
286
29227-29240
2011
Mus musculus
brenda
Urata, S.; Yun, N.; Pasquato, A.; Paessler, S.; Kunz, S.; de la Torre, J.C.
Antiviral activity of a small-molecule inhibitor of arenavirus glycoprotein processing by the cellular site 1 protease
J. Virol.
85
795-803
2011
Homo sapiens
brenda
Da Palma, J.; Burri, D.; Oppliger, J.; Salamina, M.; Cendron, L.; De Laureto, P.; Seidah, N.; Kunz, S.; Pasquato, A.
Zymogen activation and subcellular activity of subtilisin kexin isozyme 1/site 1 protease
J. Biol. Chem.
289
35743-35756
2014
Homo sapiens (Q14703)
brenda
Weiss, N.; Stegemann, A.; Elsayed, M.A.; Schallreuter, K.U.; Luger, T.A.; Loser, K.; Metze, D.; Weishaupt, C.; Boehm, M.
Inhibition of the prohormone convertase subtilisin-kexin isoenzyme-1 induces apoptosis in human melanoma cells
J. Invest. Dermatol.
134
168-175
2014
Homo sapiens (Q14703), Homo sapiens
brenda
Burri, D.; Pasqual, G.; Rochat, C.; Seidah, N.; Pasquato, A.; Kunz, S.
Molecular characterization of the processing of arenavirus envelope glycoprotein precursors by subtilisin kexin isozyme-1/site-1 protease
J. Virol.
86
4935-4946
2012
Homo sapiens (Q14703)
brenda
Burri, D.; da Palma, J.; Seidah, N.; Zanotti, G.; Cendron, L.; Pasquato, A.; Kunz, S.
Differential recognition of old world and new world arenavirus envelope glycoproteins by subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P)
J. Virol.
87
6406-6414
2013
Homo sapiens (Q14703), Homo sapiens
brenda
Sun, L.; Zhang, S.S.; Lu, S.J.; Liu, J.X.
Site-1 protease cleavage site is important for the ER stress-induced activation of membrane-associated transcription factor bZIP28 in Arabidopsis
Sci. China Life Sci.
58
270-275
2015
Arabidopsis thaliana
brenda
Patra, D.; DeLassus, E.; Mueller, J.; Abou-Ezzi, G.; Sandell, L.J.
Site-1 protease regulates skeletal stem cell population and osteogenic differentiation in mice
Biol. Open
7
bio032094
2018
Mus musculus
brenda
Nakagawa, T.; Suzuki-Nakagawa, C.; Watanabe, A.; Asami, E.; Matsumoto, M.; Nakano, M.; Ebihara, A.; Uddin, M.N.; Suzuki, F.
Site-1 protease is required for the generation of soluble (pro)renin receptor
J. Biochem.
161
369-379
2017
Cricetulus griseus
brenda
Kluender, S.; Heeren, J.; Markmann, S.; Santer, R.; Braulke, T.; Pohl, S.
Site-1 protease-activated formation of lysosomal targeting motifs is independent of the lipogenic transcription control
J. Lipid Res.
56
1625-1632
2015
Homo sapiens, Mus musculus
brenda
Schweitzer, G.; Gan, C.; Bucelli, R.; Wegner, D.; Schmidt, R.; Shinawi, M.; Finck, B.; Brookheart, R.
A mutation in Site-1 Protease is associated with a complex phenotype that includes episodic hyperCKemia and focal myoedema
Mol. Genet. Genomic Med.
2019
e733
2019
Homo sapiens
brenda
Hyrina, A.; Meng, F.; McArthur, S.J.; Eivemark, S.; Nabi, I.R.; Jean, F.
Human subtilisin kexin isozyme-1 (SKI-1)/Site-1 Protease (S1P) regulates cytoplasmic lipid droplet abundance A potential target for indirect-acting anti-dengue virus agents
PLoS ONE
12
e0174483
2017
Homo sapiens
brenda
Al-Maskari, M.; Care, M.A.; Robinson, E.; Cocco, M.; Tooze, R.M.; Doody, G.M.
Site-1 protease function is essential for the generation of antibody secreting cells and reprogramming for secretory activity
Sci. Rep.
8
14338
2018
Homo sapiens
brenda
Patra, D.; Kim, J.; Zhang, Q.; Tycksen, E.; Sandell, L.J.
Site-1 protease ablation in the osterix-lineage in mice results in bone marrow neutrophilia and hematopoietic stem cell alterations
Biol. Open
9
bio052993
2020
Mus musculus
brenda
Mousa, M.G.; Vuppaladhadiam, L.; Kelly, M.O.; Pietka, T.; Ek, S.; Shen, K.C.; Meyer, G.A.; Finck, B.N.; Brookheart, R.T.
Site-1 protease inhibits mitochondrial respiration by controlling the TGF-beta target gene Mss51
Cell Rep.
42
112336
2023
Mus musculus
brenda
Santinelli, R.; Benz, N.; Guellec, J.; Quinquis, F.; Kocas, E.; Thomas, J.; Montier, T.; Ka, C.; Luczka-Majerus, E.; Sage, E.; Ferec, C.; Coraux, C.; Trouve, P.
The inhibition of the membrane-bound transcription factor site-1 protease (MBTP1) aleviates the p.Phe508del-cystic fibrosis transmembrane conductance regulator (CFTR) Defects in cystic fibrosis cells
Cells
13
185
2024
Homo sapiens
brenda
Olaposi, O.I.; Oyekanmi, N.; Ojo, A.A.; Eniafe, G.O.
Membrane-bound transcription factor site-1 protease in PF429242 bound state Computational kinetics and dynamics of reversible binding
Drug Res.
69
643-649
2019
Homo sapiens (Q14703)
brenda
Cheng, Y.; Manabe, I.; Hayakawa, S.; Endo, Y.; Oishi, Y.
Caspase-11 contributes to site-1 protease cleavage and SREBP1 activation in the inflammatory response of macrophages
Front. Immunol.
14
1009973
2023
Homo sapiens
brenda
Wang, F.; Xu, C.; Luo, R.; Peng, K.; Ramkumar, N.; Xie, S.; Lu, X.; Zhao, L.; Zuo, C.J.; Kohan, D.E.; Yang, T.
Site-1 protease-derived soluble (pro)renin receptor targets vasopressin receptor 2 to enhance urine concentrating capability
JCI Insight
4
e124174
2019
Mus musculus
brenda
Chen, J.; Zhou, Y.; Liu, Z.; Lu, Y.; Jiang, Y.; Cao, K.; Zhou, N.; Wang, D.; Zhang, C.; Zhou, N.; Shi, K.; Zhang, L.; Zhou, L.; Wang, Z.; Zhang, H.; Tang, K.; Ma, J.; Lv, J.; Huang, B.
Hepatic glycogenesis antagonizes lipogenesis by blocking S1P via UDPG
Science
383
eadi3332
2024
Homo sapiens
brenda
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