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Information on EC 3.4.21.B6 - prostasin and Organism(s) Mus musculus and UniProt Accession Q9ESD1
for references in articles please use BRENDA:EC3.4.21.B6preliminary BRENDA-supplied EC number
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3.4.21.B6 prostasinSpecify your search results
Word Map
- 3.4.21.B6
- matriptase
- aldosterone
- hai-1
- furin
-
gpi-anchored
- aprotinin
-
amiloride-sensitive
-
glycosylphosphatidylinositol-anchored
- hepsin
- nexin-1
-
kunitz-type
- camostat
- medicine
- profilaggrin
-
enac-mediated
The taxonomic range for the selected organisms is: Mus musculus
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
prostasin, cap-1, prss8, cap1/prss8, channel-activating protease 1, channel activating protease 1, tracheal-prostasin, channel-activating protease-1, channel activating protease-1, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
CAP1
PRSS8
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CAS REGISTRY NUMBER
COMMENTARY
157857-10-8
-
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
Toll-like receptor 4 + H2O
truncated Toll-like receptor 4 + ectodomain
reduction in the full-length form and reduction of the activation of the substrate
-
-
?
epithelial sodium channel gamma subunit + H2O
?
-
the enzyme activates epithelial sodium channels by inducing cleavage of the gamma-subunit at a site distal to the furin cleavage site
-
-
?
additional information
?
-
Lys or Arg residues are amino acids targeted by the enzyme
-
-
?
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
Toll-like receptor 4 + H2O
truncated Toll-like receptor 4 + ectodomain
reduction in the full-length form and reduction of the activation of the substrate
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
bacterial lipopolysaccharide
-
downregulation of mPro mRNA expression in the bladder, upregulation of inducible nitric oxide synthase, cyclooxygenase-2, interferon-gamma, TNF-alpha, IL-1beta, and IL-6
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
matriptase
-
soluble matriptase efficiently converts soluble prostasin zymogen to an active two-chain form by endoproteolytic cleavage after Arg12 within the amino acid sequence QPR12-ITG
-
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
in polarized epithelium, matriptase and prostasin co-localize briefly at the basolateral plasma membrane prior to HAI-1-mediated matriptase endocytosis
-
simple, stratified, and pseudo-stratified epithelium of the digestive tract
-
simple, stratified, and pseudo-stratified epithelium of the integumentary system, digestive tract, respiratory tract, and urogenital tract
-
simple, stratified, and pseudo-stratified epithelium of the integumentary system
-
simple, stratified, and pseudo-stratified epithelium of the respiratory tract
-
simple, stratified, and pseudo-stratified epithelium of the urogenital tract
additional information
in nearly all murine epithelial tissues, matriptase is coexpressed with the membrane serine protease prostasin
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
prostasin contains an N-terminal secretion signal that is cleaved during intracellular transport in the endoplasmic reticulum and a GPI-anchor is attached at the C-terminal. Subsequent to surface localization, prostasin is cleaved at a conserved activation site in the pro-domain and remains attached to the serine protease domain via a disulfide bridge
prostasin is glycosylphosphatidylinositol-anchored to the cell surface
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
high-fat diet triggers the suppression of the enzyme expression by inducing endoplasmic reticulum stress and increases the Toll-like receptor 4 level in the liver. Serum enzyme levels are correlated to body mass index and homoeostasis model assessment-insulin resistance
physiological function
malfunction
prostasin null mice lack barrier formation and display fatal postnatal dehydration. But mice homozygous for a point mutation in the Prss8 gene, which causes the substitution of the active site serine within the catalytic histidine-aspartate-serine triad with alanine and renders prostasin catalytically inactive, develop barrier function and are healthy when followed for up to 20 weeks. Phenotypes, overview
physiological function
prostasin supports epidermal development and postnatal homeostasis independent of its enzymatic activity
additional information
spatial and temporal co-expression of matriptase and prostasin
malfunction
liver-specific PRSS8 enzyme knockout mice develop insulin resistance associated with the increase in hepatic Toll-like receptor 4, the knockout mice show an excessive response to lipopolysacchrides. Restoration of enzyme expression in livers of high-fat diet, knockout, and db/db mice decreases the TLR4 level and ameliorates insulin resistance, phenotypes, overview
malfunction
matriptase and prostasin null mice have identical phenotypes. mice deficient for matriptase phenocopy mice deficient for epidermal prostasin and show impaired corneocyte differentiation, imparied lipid matrix formation, loss of profilaggrin processing and loss of tight junction formation and function. Together, these defects lead to a compromised epidermal barrier and result in fatal dehydration during the neonatal period. The proteolytic processing of prostasin as well as profilaggrin is greatly reduced in matriptase hypomorphic mice
physiological function
the enzyme has the ability to activate epithelial sodium channels and effect the sodium current across the plasma membrane in vitro. In the epidermis, the glycosylphosphatidylinositol anchored membrane serine protease prostasin is activated by matriptase to initiate a proteolytic cascade that is required for the development of the stratum corneum barrier function. Proteolytic activity of the matriptase-prostasin cascade is regulated in the epidermis via inhibition by the Kunitz-type serine protease inhibitor hepatocyte growth factor activator inhibitor-1
physiological function
the serine protease prostasin regulates hepatic insulin sensitivity by modulating Toll-like receptor 4-mediated signalling, the enzyme decreases TLR4 levels by the proteolytic shedding
physiological function
knock-in mice expressing catalytically inactive prostasin display normal prenatal and postnatal survival. Catalytically inactive prostasin causes embryonic lethality in mice lacking its cognate inhibitors HAI-1 (SPINT1) or HAI-2 (SPINT2). Proteolytically inactive prostasin, unlike the wild-type protease, is unable to activate matriptase during placentation. All essential functions of prostasin in embryonic and postnatal development are compensated for by loss of HAI-1
physiological function
prostasin is found in the epidermis as one-chain zymogen and as two-chain proteolytically active form. Mice expressing only activation site cleavage-resistant (zymogen-locked) endogenous prostasin display normal interfollicular epidermal development and postnatal survival, but have defects in whisker and pelage hair formation
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). MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
from the N-terminus, prostasin comprises a pro-domain and a serine protease domain with trypsin-like activity, prostasin contains an N-terminal secretion signal that is cleaved during intracellular transport in the endoplasmic reticulum and a GPI-anchor is attached at the C-terminal
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
proteolytic modification
prostasin zymogen is incapable of auto-activation and requires proteolytic processing by a second protease, i.e. matriptase, for conversion into an active protease
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
R44Q
generation of mice expressing zymogen-locked prostasin due to lack of activation site cleavage
S313N/S314L
lacks the preferred GPI attachment sites and shows decreased activity
S313N/S314L/R322A
mutant alters both the preferred GPI attachment sites and the potential COOH-terminal tryptic cleavage site, activity is not different from wild type prostasin
additional information
construction of Prss8 knockout mutant mice. A T to G substitution, leading to substitution of the active site serine within the catalytic histidine-aspartate-serine triad with alanine, is introduced into exon 6 by site-directed mutagenesis, the clone is injected into strain C57BL/6J blastocysts
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
high-fat diet triggers the suppression of the enzyme expression by inducing endoplasmic reticulum stress
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
additional information
-
proteolytic mechanism for prostasin to intercept cytokine signaling during bacterial lipopolysaccharide-induced bladder inflammation
medicine
exogenous expression of prostasin can protect suckling mice from life-threatening DENV-2 infection. Inhibition of DENV propagation by prostasin is due to reducing expression of epithelial growth factor receptor, leading to suppression of the Akt/NF-kappaB-mediated cyclooxygenase-2 signaling pathway
medicine
mRNA and protein expression of both matriptase and prostasin are rapidly down-regulated in the initiating inflammatory phases of dextran sulfate sodium-induced experimental colitis, and the loss of these proteases precedes the appearance of clinical symptoms. Barrier disruption by the colitis-associated Th2-type cytokines, IL-4 and IL-13, down-regulates matriptase as well as prostasin through phosphorylation of the transcriptional regulator STAT6
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Liu, L.; Hering-Smith, K.S.; Schiro, F.R.; Hamm, L.L.
Serine protease activity in M-1 cortical collecting duct cells
Hypertension
39
860-864
2002
Mus musculus
Chen, L.M.; Wang, C.; Chen, M.; Marcello, M.R.; Chao, J.; Chao, L.; Chai, K.X.
Prostasin attenuates inducible nitric oxide synthase expression in lipopolysaccharide-induced urinary bladder inflammation
Am. J. Physiol. Renal Physiol.
291
F567-F577
2006
Homo sapiens (Q16651), Homo sapiens, Mus musculus
Chao, J.
Prostasin
Handbook of Proteolytic Enzymes (Barrett, A. J. , Rawlings, N. D. , Woessner, J. F. , Eds. ) Academic Press
2
1708-1709
2004
Homo sapiens, Mus musculus, Rattus norvegicus, Xenopus laevis
-
Verghese, G.M.; Gutknecht, M.F.; Caughey, G.H.
Prostasin regulates epithelial monolayer function: cell-specific Gpld1-mediated secretion and functional role for GPI anchor
Am. J. Physiol.
291
C1258-C1270
2006
Mus musculus (Q99L44), Mus musculus
Netzel-Arnett, S.; Currie, B.M.; Szabo, R.; Lin, C.Y.; Chen, L.M.; Chai, K.X.; Antalis, T.M.; Bugge, T.H.; List, K.
Evidence for a matriptase-prostasin proteolytic cascade regulating terminal epidermal differentiation
J. Biol. Chem.
281
32941-32945
2006
Mus musculus
Bruns, J.B.; Carattino, M.D.; Sheng, S.; Maarouf, A.B.; Weisz, O.A.; Pilewski, J.M.; Hughey, R.P.; Kleyman, T.R.
Epithelial Na+ channels are fully activated by furin- and prostasin-dependent release of an inhibitory peptide from the gamma-subunit
J. Biol. Chem.
282
6153-6160
2007
Mus musculus
List, K.; Hobson, J.P.; Molinolo, A.; Bugge, T.H.
Co-localization of the channel activating protease prostasin/(CAP1/PRSS8) with its candidate activator, matriptase
J. Cell. Physiol.
213
237-245
2007
Mus musculus
Miller, G.S.; List, K.
The matriptase-prostasin proteolytic cascade in epithelial development and pathology
Cell Tissue Res.
351
245-253
2013
Mus musculus (Q9ESD1)
Peters, D.E.; Szabo, R.; Friis, S.; Shylo, N.A.; Uzzun Sales, K.; Holmbeck, K.; Bugge, T.H.
The membrane-anchored serine protease prostasin (CAP1/PRSS8) supports epidermal development and postnatal homeostasis independent of its enzymatic activity
J. Biol. Chem.
289
14740-14749
2014
Mus musculus (Q99L44), Mus musculus C57BL/6N (Q99L44)
Uchimura, K.; Hayata, M.; Mizumoto, T.; Miyasato, Y.; Kakizoe, Y.; Morinaga, J.; Onoue, T.; Yamazoe, R.; Ueda, M.; Adachi, M.; Miyoshi, T.; Shiraishi, N.; Ogawa, W.; Fukuda, K.; Kondo, T.; Matsumura, T.; Araki, E.; Tomita, K.; Kitamura, K.
The serine protease prostasin regulates hepatic insulin sensitivity by modulating TLR4 signalling
Nat. Commun.
5
3428
2014
Homo sapiens (Q16651), Mus musculus (Q9ESD1)
Szabo, R.; Lantsman, T.; Peters, D.E.; Bugge, T.H.
Delineation of proteolytic and non-proteolytic functions of the membrane-anchored serine protease prostasin
Development
143
2818-2828
2016
Mus musculus (Q9ESD1), Mus musculus
Friis, S.; Madsen, D.H.; Bugge, T.H.
Distinct developmental functions of prostasin (CAP1/PRSS8) zymogen and activated prostasin
J. Biol. Chem.
291
2577-2582
2016
Mus musculus (Q9ESD1)
Buzza, M.S.; Johnson, T.A.; Conway, G.D.; Martin, E.W.; Mukhopadhyay, S.; Shea-Donohue, T.; Antalis, T.M.
Inflammatory cytokines down-regulate the barrier-protective prostasin-matriptase proteolytic cascade early in experimental colitis
J. Biol. Chem.
292
10801-10812
2017
Homo sapiens (Q16651), Homo sapiens, Mus musculus (Q9ESD1)
Lin, C.K.; Tseng, C.K.; Wu, Y.H.; Lin, C.Y.; Huang, C.H.; Wang, W.H.; Liaw, C.C.; Chen, Y.H.; Lee, J.C.
Prostasin impairs epithelial growth factor receptor activation to suppress Dengue virus propagation
J. Infect. Dis.
219
1377-1388
2019
Homo sapiens (Q16651), Homo sapiens, Mus musculus (Q9ESD1)
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