Information on EC 3.4.24.85 - S2P endopeptidase

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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea

EC NUMBER
COMMENTARY
3.4.24.85
-
RECOMMENDED NAME
GeneOntology No.
S2P endopeptidase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
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.
show the reaction diagram
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REACTION TYPE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
hydrolysis of peptide bond
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SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
intramembrane-cleaving protease
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proteinase, sterol regulatory element-binding protein
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site-1 protease
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site-2 protease
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site-2 protease
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site-2 protease
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site-2 protease
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site-2 protease
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site-2 protease
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site-2 protease
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site-2 protease
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site-2 protease
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site-2 protease
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site-2 protease
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site-2 protease
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site-2 protease
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site-2 protease
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SREBP cleavage activity
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SREBP cysteine proteinase
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SREBP proteinase
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SREBP-1 proteinase
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SREBP-2 proteinase
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SREBP-2 proteinase
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SREBP-2 proteinase
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SREBP-2 proteinase
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SREBP-2 proteinase
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SREBP-2 proteinase
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SREBP-2 proteinase
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SREBP-2 proteinase
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sterol regulatory element binding protein
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sterol regulatory element binding protein-2 proteinase
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sterol regulatory element-binding proteinase
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sterol-regulated protease
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CAS REGISTRY NUMBER
COMMENTARY
167140-48-9
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752251-31-3
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ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
Chinese hamster, s2p cloned
SwissProt
Manually annotated by BRENDA team
yaeL cloned
GenBank
Manually annotated by BRENDA team
recombinant enzyme
-
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Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
physiological function
-
the enzyme is involved in activation of the crucial membrane-associated transcription factors deltaK during sporulation
physiological function
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HurP is essential for heme-dependent induction of bhuR and downstream genes
physiological function
-
the enzyme is involved in the production of pheromone cAD1, cPD1, and cCF10, and inhibitor peptide iAD1 and iCF10.The enzyme processes the sex pheromone and inhibitor precursors as they pass through the cell membrane
physiological function
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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
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RasP is involved in transmembrane stress signal transduction
physiological function
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RseP introduces a cleavage into signal peptides after their signal peptidase-mediated liberation from preproteins. The enzyme is involved in degradation of remnant signal peptides left in the bacterial cytoplasmic membrane
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ATF-6 + H2O
?
show the reaction diagram
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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
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?
ATF6 + H2O
?
show the reaction diagram
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?
ATF6 + H2O
?
show the reaction diagram
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-
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?
ATF6 + H2O
?
show the reaction diagram
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cleavage in site-2 is required for induction of IRE1-alpha and ER-stress activated target genes
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?
ATF6 protein + H2O
?
show the reaction diagram
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?
beta-lactamase signal peptide + H2O
?
show the reaction diagram
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cleaves within the hydrophobic core at Pro12-Phe13. Cleavage of signal peptide requires a preceding processing of preproteins by Lep
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?
cAD1 pheromone + H2O
?
show the reaction diagram
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?
cAD1 protein + H2O
?
show the reaction diagram
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?
cCF10 protein + H2O
?
show the reaction diagram
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-
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?
cPD1 protein + H2O
?
show the reaction diagram
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-
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?
CREBH protein + H2O
?
show the reaction diagram
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?
FtsL protein + H2O
?
show the reaction diagram
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-
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?
HurR protein + H2O rasp
?
show the reaction diagram
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-
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?
iAD1 protein + H2O
?
show the reaction diagram
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?
iCF10 protein + H2O
?
show the reaction diagram
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?
MSIQHFRVALIPFFAAFCLPVFA + H2O
MSIQHFRVALIP + FFAAFCLPVFA
show the reaction diagram
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?
MtuA protein + H2O
?
show the reaction diagram
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?
MucA protein + H2O pseudo
?
show the reaction diagram
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?
OASIS protein + H2O
?
show the reaction diagram
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?
PBP3 protein + H2O rasp
?
show the reaction diagram
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?
PodJ protein + H2O
?
show the reaction diagram
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?
PodJS + H2O
?
show the reaction diagram
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truncated form of transmembrane protein PodJ which provides the spatial cues for biogenesis of several polar organelles. Enzyme cleaves within or near the transmembrane segment of PodJS releasing it into cytoplasm for complete proteolysis
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?
pro-deltaK protein + H2O
deltaK protein + N-terminal fragment of 20 amino acids of pro-deltaK protein
show the reaction diagram
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?
pro-sigma K + H2O
?
show the reaction diagram
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?
RseA protein + H2O
?
show the reaction diagram
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?
RsiW protein + H2O
?
show the reaction diagram
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?
Sre1 protein + H2O
?
show the reaction diagram
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?
SREBP NH2-522 fragment + H2O
NH2-484 fragment + 38 aa fragment
show the reaction diagram
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?
SREBP NH2-522 fragment + H2O
NH2-484 fragment + 38 aa fragment
show the reaction diagram
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?
SREBP NH2-522 fragment + H2O
NH2-484 fragment + 38 aa fragment
show the reaction diagram
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-
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?
SREBP NH2-522 fragment + H2O
NH2-484 fragment + 38 aa fragment
show the reaction diagram
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-
-
-
?
SREBP NH2-522 fragment + H2O
NH2-484 fragment + 38 aa fragment
show the reaction diagram
-
-
-
-
?
SREBP NH2-522 fragment + H2O
NH2-484 fragment + 38 aa fragment
show the reaction diagram
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-
-
-
?
SREBP NH2-522 fragment + H2O
NH2-484 fragment + 38 aa fragment
show the reaction diagram
-
-
-
-
?
SREBP NH2-522 fragment + H2O
NH2-484 fragment + 38 aa fragment
show the reaction diagram
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-
-
-
?
SREBP NH2-522 fragment + H2O
NH2-484 fragment + 38 aa fragment
show the reaction diagram
-
-
-
-
?
SREBP NH2-522 fragment + H2O
NH2-484 fragment + 38 aa fragment
show the reaction diagram
-
-
-
-
?
SREBP NH2-522 fragment + H2O
NH2-484 fragment + 38 aa fragment
show the reaction diagram
-
-
-
-
?
SREBP NH2-522 fragment + H2O
NH2-484 fragment + 38 aa fragment
show the reaction diagram
-
-
-
-
?
SREBP NH2-522 fragment + H2O
NH2-484 fragment + 38 aa fragment
show the reaction diagram
-
-
-
-
?
SREBP NH2-522 fragment + H2O
NH2-484 fragment + 38 aa fragment
show the reaction diagram
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-
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?
SREBP NH2-522 fragment + H2O
NH2-484 fragment + 38 aa fragment
show the reaction diagram
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-, cleavage at site-2 between 484-485 aa of SREBP cannot occur without prior cleavage at site-1 and is dependent on 478DRSR sequence
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?
sterol regulatory element binding protein + H2O
?
show the reaction diagram
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?
TcpP protein + H2O
?
show the reaction diagram
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?
LivK signal peptide + H2O
?
show the reaction diagram
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?
additional information
?
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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
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additional information
?
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YaeL is required for the activation of sigma factor E in response to stress by site-2 cleavage of RseA that acts as an anti-sigma factor E
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
ATF6 + H2O
?
show the reaction diagram
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?
ATF6 protein + H2O
?
show the reaction diagram
-
-
-
-
?
beta-lactamase signal peptide + H2O
?
show the reaction diagram
-
cleaves within the hydrophobic core at Pro12-Phe13. Cleavage of signal peptide requires a preceding processing of preproteins by Lep
-
-
?
cAD1 protein + H2O
?
show the reaction diagram
-
-
-
-
?
cCF10 protein + H2O
?
show the reaction diagram
-
-
-
-
?
cPD1 protein + H2O
?
show the reaction diagram
-
-
-
-
?
CREBH protein + H2O
?
show the reaction diagram
-
-
-
-
?
FtsL protein + H2O
?
show the reaction diagram
-
-
-
-
?
HurR protein + H2O rasp
?
show the reaction diagram
-
-
-
-
?
iAD1 protein + H2O
?
show the reaction diagram
-
-
-
-
?
iCF10 protein + H2O
?
show the reaction diagram
-
-
-
-
?
LivK signal peptide + H2O
?
show the reaction diagram
-
-
-
-
?
MSIQHFRVALIPFFAAFCLPVFA + H2O
MSIQHFRVALIP + FFAAFCLPVFA
show the reaction diagram
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-
-
-
?
MtuA protein + H2O
?
show the reaction diagram
-
-
-
-
?
MucA protein + H2O pseudo
?
show the reaction diagram
-
-
-
-
?
OASIS protein + H2O
?
show the reaction diagram
-
-
-
-
?
PBP3 protein + H2O rasp
?
show the reaction diagram
-
-
-
-
?
PodJ protein + H2O
?
show the reaction diagram
-
-
-
-
?
PodJS + H2O
?
show the reaction diagram
-
truncated form of transmembrane protein PodJ which provides the spatial cues for biogenesis of several polar organelles. Enzyme cleaves within or near the transmembrane segment of PodJS releasing it into cytoplasm for complete proteolysis
-
-
?
pro-deltaK protein + H2O
deltaK protein + N-terminal fragment of 20 amino acids of pro-deltaK protein
show the reaction diagram
-
-
-
-
?
RseA protein + H2O
?
show the reaction diagram
-
-
-
-
?
RsiW protein + H2O
?
show the reaction diagram
-
-
-
-
?
Sre1 protein + H2O
?
show the reaction diagram
-
-
-
-
?
SREBP NH2-522 fragment + H2O
NH2-484 fragment + 38 aa fragment
show the reaction diagram
-
-
-
?
sterol regulatory element binding protein + H2O
?
show the reaction diagram
-
-
-
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?
COFACTOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
Zn
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zinc metalloprotease
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
1,10-phenanthroline
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1,10-phenanthroline specifically inhibits substrate cleavage in a concentration-dependent manner
cholesterol
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inhibits the first cleavage of SREBP and indirectly S2P cleavage
additional information
-
gamma-sectretase inhibitor LY411575 is not inhibitory for enzyme
-
additional information
-
SpoIVFB is held inactive by two other integral-membrane proteins, SpoIVFA and BofA
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ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
homocysteine
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thapsigargin
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cells treated with thapsigargin exhibit proteolytic cleavage of SREBP-2
Tunicamycin
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SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
additional information
-
-
validation of cellular assay for enzyme and S1P endopeptidase activity based on release of N-terminus of sterol regulatory element binding protein driving the expression of a luciferase reporter gene
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
O54862
CHO-7 and M19 S2P deficient cell lines
Manually annotated by BRENDA team
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CHO-K1 wild type and M19 S2P deficient cell lines
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
transmembrane protein YaeL has the consensus metal-binding site
-
Manually annotated by BRENDA team
-
transmembrane protein
Manually annotated by BRENDA team
-
colocalization with S1P endopepetidase in cis/medial Golgi
Manually annotated by BRENDA team
additional information
-
enzyme is unifirmly distributed around the cell and present throughout the cell cycle
-
Manually annotated by BRENDA team
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
?
-
x * 45000, SDS-PAGE
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
expressed in CHO cell line
O54862
expressed in pKK10 and pKK11 plasmid
-
expressed in pKK6
-
expressed in M19 cell line
-
expressed in Escherichia coli
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ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
D402N
-
abolished activity
E23Q
-
abolished activity
H22F
-
abolished activity
H22F
-
active site mutant
H26F
-
abolished activity
N337Q
-
mutation at glycosylation site N337 does not abolish activity
N508Q
-
mutation does not abolish activity
D148A
-
mutant exhibits markedly compromised protease activity
E55A
-
mutant exhibits markedly compromised protease activity
H54A
-
mutant exhibits markedly compromised protease activity
H54A/D148A
-
mutant exhibits markedly compromised protease activity
H58A
-
mutant exhibits markedly compromised protease activity
H22F
-
active site mutant
additional information
O54862
M19 mutant cell line of CHO-K1 cells with no s2p activity
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
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
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