Information on EC 3.4.23.B24 - signal peptide peptidase

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

EC NUMBER
COMMENTARY hide
3.4.23.B24
preliminary BRENDA-supplied EC number
RECOMMENDED NAME
GeneOntology No.
signal peptide peptidase
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
intramembrane cleavage of signal peptides
show the reaction diagram
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-
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
dodecanoyl-NGEVAKA-4-methylcumaryl-7-amide + H2O
?
show the reaction diagram
heat shock protein 101 + H2O
?
show the reaction diagram
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-
-
?
heme oxygenase-1 + H2O
?
show the reaction diagram
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signal peptide peptidase SPP catalyzes the intramembrane cleavage of heme oxygenase-1. Two adjacent intramembrane cleavage sites are located after S275 and F276 within the trans membrane segment
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?
myc-prolactin-PP-Flag peptide + H2O
?
show the reaction diagram
human signal peptide peptidase substrate
migration of the fragments that are cleaved in SDS-PAGE is identical in size to the fragments produced by human signal peptide peptidase
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?
unfolded protein response regulator XBP1u + H2O
?
show the reaction diagram
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cleavage occurs within a so far unrecognized type II transmembrane domain, which renders XBP1u as an signal peptide peptidase substrate through specific sequence features
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additional information
?
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
additional information
?
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SPP interacts specifically and tightly with a large range of newly synthesized membrane proteins, including signal peptides, preproteins and misfolded membrane proteins, but not with all co-expressed type II membrane proteins. Preproteins and misfolded membrane proteins interact with SPP, and are not substrates for SPP-mediated intramembrane proteolysis. Proteins interacting with SPP are found in distinct complexes of different sizes. A signal peptide is mainly trapped in a 200 kDa SPP complex, whereas a preprotein is predominantly found in a 600 kDa SPP complex. A misfolded membrane protein is detected in 200, 400 and 600 kDa SPP complexes. SPP not only processes signal peptides, but also collects preproteins and misfoldedmembrane proteins that are destined for disposal
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1,3-di-(N-carboxybenzoyl-L-leucyl-L-leucyl) amino acetone
NH3-SPRMMYLYAK-COOH
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peptide synthesized corresponding to the sequence of the modeled C-terminal peptide bound in the SppA substrate-binding groove. Competitive inhibition
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[(2R,4R,5S)-2-benzyl-5-(t-butyloxycarbonylamino)-4-hydroxy-6-phenylhexanoyl]-L-leucyl-L-phenylalanine amide
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0179
dodecanoyl-NGEVAKA-4-methylcumaryl-7-amide
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pH 8.0, 23°C
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.078
dodecanoyl-NGEVAKA-4-methylcumaryl-7-amide
Bacillus subtilis
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pH 8.0, 23°C
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0021
NH3-SPRMMYLYAK-COOH
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pH 8.0, 23°C
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
n-dodecyl-beta-maltoside-solubilized membrane fraction
Manually annotated by BRENDA team
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
26624
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x * 26624, electrospray ionization mass spectrometry of protease resistant fragment Leu51-Gly295
28000
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8 * 36000, SDS-PAGE. 8 * 28000, SDS-PAGE after limited digestion using thermolysin
35000
1 * 35000, SDS-PAGE, and dimer; 2 * 35000, SDS-PAGE, and monomer
36000
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8 * 36000, SDS-PAGE. 8 * 28000, SDS-PAGE after limited digestion using thermolysin
225400
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gel filtration
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
2 * 35000, SDS-PAGE, and monomer
monomer
1 * 35000, SDS-PAGE, and dimer
octamer
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
2.4-A resolution structure of Bacillus subtilis SppA catalytic domain reveals eight SppA molecules in the asymmetric unit, forming a dome-shaped octameric complex. Residue Ser147 may serve as the nucleophile and Lys199 may serve as the general base. The SppA S1 substrate specificity pocket is deep, narrow and hydrophobic, but with a polar bottom. The S3 pocket, which is constructed from two neighboring proteins, is shallower, wider and more polar than the S1 pocket
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crystal structure of a proteolytically stable fragment of mutant K199A, residues Leu51-Gly295, that has its C-terminal peptide bound in each of the eight active sites, creating a perfect circle of peptides. Substrate specificity pockets accommodate C-terminal residues Tyr331, Met329, and Tyr333, respectively. The C-terminus binds within the substrate-binding grooves in an antiparallel beta-sheet fashion
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expression in HEK-293 cell
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expression in HEK-293T cell
expression in Saccharomyces cerevisiae
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
S147A
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inactive
K199A
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active site mutant; inactive
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S147A
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inactive
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D265A
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inactive. Signal peptides are trapped by the catalytically inactive SPP mutant. Preproteins and misfolded membrane proteins interact with both wild-type SPP and the mutant
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
analysis
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application of the photophore walking technique for probing the active sites of SPP. Nontransition state gamma-secretase inhibitors inhibit labeling of gamma-secretase by activity-based probes but enhance labeling of SPP. The opposite is true of gamma secretase modulators, which have little effect on the labeling of gamma-secretase but diminish labeling of SPP
medicine