Any feedback?
Information on EC 3.4.24.85 - S2P endopeptidase and Organism(s) Homo sapiens and UniProt Accession O43462
for references in articles please use BRENDA:EC3.4.24.85Please wait a moment until all data is loaded. This message will disappear when all data is loaded.
EC Tree
3.4.24.85 S2P endopeptidaseSpecify your search results
Word Map
- 3.4.24.85
- cholesterol
-
srebps
- triglyceride
- peroxisome
- lipoprotein
-
lipogenesis
- srebp-1c
-
lipogenic
-
proliferator-activated
- steatosis
- adipose
- obesity
- acetyl-coa
-
high-fat
- adipocyte
-
desaturase
- hepatocytes
-
low-density
- carnitine
-
obese
- stearoyl-coa
-
amp-activated
-
diet-induced
-
site-1
- proliferator
-
hfd-induced
-
cleavage-activating
-
nonalcoholic
- adiponectin
- hyperlipidemia
- nafld
-
stearoyl
-
forespore
-
presenilins
-
niemann-pick
-
3-hydroxy-3-methylglutaryl
- sigmak
- gamma-secretase
-
membrane-embedded
- atf6
- rhomboid
-
anti-adipogenic
- medicine
-
chrebp
- acaca
- synthesis
-
palmitoyltransferase-1
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Archaea, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Archaea, Bacteria
Reaction Schemes
Cleaves several transcription factors that are type-2 transmembrane proteins within membrane-spanning domains. Known substrates include sterol regulatory element-binding protein (SREBP) -1, SREBP-2 and forms of the transcriptional activator ATF6. SREBP-2 is cleaved at the site DRSR_ILL_483-/-CVLTFLCLSFNPLTSLLQWGGA, in which the membrane-spanning segment is underlined. The residues NP (bold), 11 residues distal to the site of cleavage in the membrane-spanning domain, are important for cleavage by S2P endopeptidase. Replacement of either of these residues does not prevent cleavage, but there is no cleavage if both of these residues are replaced.
Synonyms
sterol regulatory element binding protein, spoivfb, site-2 protease, intramembrane-cleaving protease, i-clip, sll0528, slr0643, sterol-regulated protease, site-2-protease, site-2 metalloprotease, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
proteinase, sterol regulatory element-binding protein
-
-
-
-
site-1 protease
-
-
-
-
site-2 protease
SREBP cleavage activity
-
-
-
-
SREBP cysteine proteinase
-
-
-
-
SREBP proteinase
-
-
-
-
SREBP-1 proteinase
-
-
-
-
SREBP-2 proteinase
sterol regulatory element-binding proteinase
-
-
-
-
sterol-regulated protease
-
-
-
-
site-2 protease
-
-
-
-
SREBP-2 proteinase
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
167140-48-9
-
752251-31-3
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATF-6 + H2O
?
-
endoplasmic reticulum membrane-anchored transcription factor, sequential processing by enzyme and S1P endopeptidase. Bulky ATF6 luminal domain blocks cleavage by enzyme, cleavage by S1P endopeptidase reduces the size of the luminal domain and prepares for hydrolysis by enzyme
-
-
?
CED-9 + H2O
?
-
artificial protein substrate, Caenorhabditis elegans protein 9, homolog to human Bcl-2
-
-
?
additional information
?
-
SREBP asparagine-495 and proline-496 seem to be necessary for cleavage by S2P, and it is conserved in all known SREBPs, the movement of the NP sequence within the transmembrane domain does not eliminate cleavage, nor does it change the site of cleavage
-
-
?
SREBP NH2-522 fragment + H2O
NH2-484 fragment + 38 aa fragment
-
-
?
SREBP NH2-522 fragment + H2O
NH2-484 fragment + 38 aa fragment
cleavage at site-2 between 484-485 aa of SREBP cannot occur without prior cleavage at site-1 and is dependent on 478DRSR sequence
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
SREBP NH2-522 fragment + H2O
NH2-484 fragment + 38 aa fragment
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
cholesterol
inhibits the first cleavage of SREBP and indirectly S2P cleavage
(2E)-N-(2-[[3-(3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)propyl]sulfanyl]phenyl)-3-phenylprop-2-enamide
-
-
1-[(benzoylamino)methyl]-1-[3-(benzylsulfanyl)-1-methoxy-1-oxopropan-2-yl]-4-[(benzylsulfanyl)methyl]-2,5-dioxoimidazolidin-1-ium
-
-
3-(butan-2-yl)-8-[3-[(4-fluorophenyl)sulfanyl]propyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one
-
-
methyl 4-[[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-oxobutyl]sulfanyl]benzoate
-
-
7,8-dimethoxy-1,2,3,11a-tetrahydro-5H,11H-pyrrolo[2,1-c][1,4]benzothiazepine-5,11-dione
-
-
7,8-dimethoxy-1,2,3,11a-tetrahydro-5H,11H-pyrrolo[2,1-c][1,4]benzothiazepine-5,11-dione
-
analog of nelfinavir, inhibits cleavage of artificial protein substrate CED-9 in an in vitro proteolysis assay. Inhibits castration-resistant prostate cancer proliferation by blocking regulated intramembrane proteolysis through suppression of site-2 protease cleavage activity
nelfinavir
-
nelfinavir and its analogs inhibit cleavage of artificial protein substrate CED-9 in an in vitro proteolysis assay. Nelfinavir and its analogs inhibit castration-resistant prostate cancer proliferation by blocking regulated intramembrane proteolysis through suppression of site-2 protease cleavage activity
nelfinavir
-
nelfinavir is a more potent inhibitor of CED-9 protein cleavage than 1,10-phenanthroline
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
thapsigargin
-
cells treated with thapsigargin exhibit proteolytic cleavage of SREBP-2
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
colocalization with S1P endopepetidase in cis/medial Golgi
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
physiological function
-
the enzyme is involved in the feedback regulation of sterol and fatty acid synthesis and uptake by controlling the activity of transcription factors, sterol regulatory element binding proteins. Through the S2P cascade, the cholesterol feedback pathway in humans is stringently regulated
physiological function
-
the enzyme is the molecular target for baicalin in inducing endoplasmic reticulum stress-mediated hepatocellular carcinoma cell apoptosis
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). MBTP2_HUMAN
519
6
57444
Swiss-Prot
Secretory Pathway (Reliability: 1)
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D467N
mutation of aspartate abolish activity suggesting that is the third residue that coordinates the zinc active site of S2P
additional information
mutants in any of the histidines for phenylalanine or glutamic acid for alanine of the consensus metal-binding site abolished activity
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
synthesis
in absence of cholesterol, SREBP double cleavage leads to activation of transcription of genes encoding multiple enzymes of the cholesterol biosynthetic pathway
medicine
-
nelfinavir and its analogs inhibit castration-resistant prostate cancer proliferation by blocking regulated intramembrane proteolysis through suppression of site-2 protease cleavage activity. This leads to accumulation of precursors of sterol regulatory element-binding protein SREBP-1 and activating transcription factor ATF6, and development of insufficient reserves of their transcriptionally-active forms
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Rawson, R.; Zelenski, N.; Nijhawan, D.; Ye, J.; Sakai, J.; Hasan, M.; Chang, T.; Brown, M.; Goldstein, J.
Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs
Mol. Cell
1
47-57
1997
Homo sapiens (O43462), Cricetulus griseus (O54862)
Zelenski, N.; Rawson, R.; Brown, M.; Goldstein, J.
Membrane topology of S2P, a protein required for intramembranous cleavage of sterol regulatory element-binding proteins
J. Biol. Chem.
274
21973-21980
1999
Homo sapiens (O43462)
Brown, M.; Ye, J.; Rawson, R.; Goldstein, J.
Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans
Cell
100
391-398
2000
Homo sapiens (O43462)
Ye, J.; Dav, U.; Grishin, N.; Goldstein, J.; Brown, M.
Asparagine-proline sequence within membrane-spanning segment of SREBP triggers intramembrane cleavage by site-2 protease
Proc. Natl. Acad. Sci. USA
97
5123-5128
2000
Homo sapiens (O43462)
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
Colgan, S.M.; Tang, D.; Werstuck, G.H.; Austin, R.C.
Endoplasmic reticulum stress causes the activation of sterol regulatory element binding protein-2
Int. J. Biochem. Cell Biol.
39
1843-1851
2007
Homo sapiens
Kinch, L.N.; Ginalski, K.; Grishin, N.V.
Site-2 protease regulated intramembrane proteolysis: Sequence homologs suggest an ancient signaling cascade
Protein Sci.
15
84-93
2006
Synechocystis sp., Arabidopsis thaliana, Halalkalibacterium halodurans, Caenorhabditis elegans, Deinococcus radiodurans, Drosophila melanogaster, Escherichia coli, Giardia intestinalis, Halobacterium sp., Homo sapiens, Methanothermobacter thermautotrophicus, Mycobacterium leprae, Plasmodium falciparum, Pyrobaculum aerophilum, Thermoplasma volcanium, Thermotoga maritima, Treponema pallidum
Chen, G.; Zhang, X.
New insights into S2P signaling cascades: regulation, variation and conservation
Protein Sci.
19
2015-2030
2010
Bordetella bronchiseptica, Bacillus subtilis, Caulobacter vibrioides, Cryptococcus neoformans, Escherichia coli, Enterococcus faecalis, Homo sapiens, Methanocaldococcus jannaschii, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Streptococcus uberis
Guan, M.; Fousek, K.; Chow, W.A.
Nelfinavir inhibits regulated intramembrane proteolysis of sterol regulatory element binding protein-1 and activating transcription factor 6 in castration-resistant prostate cancer
FEBS J.
279
2399-2411
2012
Homo sapiens
Yu, Z.; Luo, X.; Wang, C.; Ye, J.; Liu, S.; Xie, L.; Wang, F.; Bao, J.
Baicalin promoted site-2 protease and not site-1 protease in endoplasmic reticulum stress-induced apoptosis of human hepatocellular carcinoma cells
FEBS Open Bio
6
1093-1101
2016
Homo sapiens
EXTERNAL LINKS (specific for EC-Number 3.4.24.85)
Use of this online version of BRENDA is free under the CC BY 4.0 license. See terms of use for full details.
Release 2023.1 (January 2023)
Legal
Curated at
Member of
