UniProt functional annotation for P09958



	UniProt functional annotation for P09958

UniProt code: P09958.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Ubiquitous endoprotease within constitutive secretory pathways capable of cleavage at the RX(K/R)R consensus motif (PubMed:11799113, PubMed:1629222, PubMed:1713771, PubMed:2251280, PubMed:24666235, PubMed:25974265, PubMed:7592877, PubMed:7690548, PubMed:9130696). Mediates processing of TGFB1, an essential step in TGF-beta-1 activation (PubMed:7737999). Converts through proteolytic cleavage the non-functional Brain natriuretic factor prohormone into its active hormone BNP(1-32) (PubMed:20489134, PubMed:21763278). {ECO:0000269|PubMed:11799113, ECO:0000269|PubMed:1629222, ECO:0000269|PubMed:1713771, ECO:0000269|PubMed:20489134, ECO:0000269|PubMed:21763278, ECO:0000269|PubMed:2251280, ECO:0000269|PubMed:24666235, ECO:0000269|PubMed:25974265, ECO:0000269|PubMed:7592877, ECO:0000269|PubMed:7690548, ECO:0000269|PubMed:7737999, ECO:0000269|PubMed:9130696}.

Function: (Microbial infection) Cleaves and activates diphtheria toxin DT. {ECO:0000269|PubMed:8253774}.

Function: (Microbial infection) Cleaves and activates anthrax toxin protective antigen (PA). {ECO:0000269|PubMed:1438214, ECO:0000269|PubMed:1644824}.

Function: (Microbial infection) Required for H7N1 and H5N1 influenza virus infection probably by cleaving hemagglutinin. {ECO:0000269|PubMed:25974265}.

Function: (Microbial infection) Able to cleave S.pneumoniae serine-rich repeat protein PsrP. {ECO:0000269|PubMed:27582320}.

Function: (Microbial infection) Facilitates human coronaviruses EMC and SARS-CoV-2 infections by proteolytically cleaving the spike protein at the monobasic S1/S2 cleavage site. This cleavage is essential for spike protein-mediated cell-cell fusion and entry into human lung cells. {ECO:0000269|PubMed:32362314}.

Catalytic activity: Reaction=Release of mature proteins from their proproteins by cleavage of -Arg-Xaa-Yaa-Arg-|-Zaa- bonds, where Xaa can be any amino acid and Yaa is Arg or Lys. Releases albumin, complement component C3 and von Willebrand factor from their respective precursors.; EC=3.4.21.75; Evidence={ECO:0000269|PubMed:11799113, ECO:0000269|PubMed:1438214, ECO:0000269|PubMed:1629222, ECO:0000269|PubMed:1644824, ECO:0000269|PubMed:1713771, ECO:0000269|PubMed:2251280, ECO:0000269|PubMed:24666235, ECO:0000269|PubMed:25974265, ECO:0000269|PubMed:32362314, ECO:0000269|PubMed:7592877, ECO:0000269|PubMed:7690548, ECO:0000269|PubMed:7737999, ECO:0000269|PubMed:8253774, ECO:0000269|PubMed:9130696};

Cofactor: Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000269|PubMed:1644824, ECO:0000269|PubMed:24666235, ECO:0000269|PubMed:25974265, ECO:0000269|PubMed:9130696}; Note=Binds 3 calcium ions per subunit. {ECO:0000269|PubMed:24666235, ECO:0000269|PubMed:25974265, ECO:0000269|PubMed:9130696};

Activity regulation: Inhibited by the not secondly cleaved propeptide (PubMed:9130696, PubMed:11799113). Inhibited by m-guanidinomethyl- phenylacetyl-Arg-Val-Arg-(amidomethyl)-benzamidine (m-guanidinomethyl- Phac-RVR-Amb) and 4-guanidinomethyl-phenylacetyl-Arg-Tle-Arg-4- amidinobenzylamide (MI-1148) (PubMed:24666235, PubMed:25974265). Inhibited by Decanoyl-Arg-Val-Lys-Arg-chloromethylketone (decanoyl- RVKR-CMK) (PubMed:32362314). {ECO:0000269|PubMed:11799113, ECO:0000269|PubMed:24666235, ECO:0000269|PubMed:25974265, ECO:0000269|PubMed:32362314, ECO:0000269|PubMed:9130696}.

Biophysicochemical properties: pH dependence: Optimum pH is 6.0. {ECO:0000269|PubMed:9130696};

Subunit: Interacts with FLNA (By similarity). Binds to PACS1 which mediates TGN localization and connection to clathrin adapters (PubMed:11331585). {ECO:0000250|UniProtKB:P23188, ECO:0000269|PubMed:11331585}.

Subcellular location: Golgi apparatus, trans-Golgi network membrane {ECO:0000269|PubMed:11331585, ECO:0000269|PubMed:11799113, ECO:0000269|PubMed:8846780, ECO:0000269|PubMed:9130696, ECO:0000269|PubMed:9412467}; Single-pass type I membrane protein {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:11799113, ECO:0000269|PubMed:9130696, ECO:0000269|PubMed:9412467}; Single-pass type I membrane protein {ECO:0000305}. Secreted {ECO:0000305|PubMed:11799113}. Endosome membrane {ECO:0000269|PubMed:9412467}; Single-pass type I membrane protein {ECO:0000305}. Note=Shuttles between the trans-Golgi network and the cell surface (PubMed:9412467, PubMed:11799113). Propeptide cleavage is a prerequisite for exit of furin molecules out of the endoplasmic reticulum (ER). A second cleavage within the propeptide occurs in the trans Golgi network (TGN), followed by the release of the propeptide and the activation of furin (PubMed:11799113). {ECO:0000269|PubMed:11799113, ECO:0000269|PubMed:9412467}.

Tissue specificity: Seems to be expressed ubiquitously. {ECO:0000269|PubMed:1713771}.

Domain: Contains a cytoplasmic domain responsible for its TGN localization and recycling from the cell surface. {ECO:0000269|PubMed:8846780}.

Ptm: The inhibition peptide, which plays the role of an intramolecular chaperone, is autocatalytically removed in the endoplasmic reticulum (ER) and remains non-covalently bound to furin as a potent autoinhibitor. Following transport to the trans Golgi, a second cleavage within the inhibition propeptide results in propeptide dissociation and furin activation. {ECO:0000269|PubMed:1629222, ECO:0000269|PubMed:9130696}.

Ptm: Phosphorylation is required for TGN localization of the endoprotease. In vivo, exists as di-, mono- and non-phosphorylated forms. {ECO:0000269|PubMed:8846780}.

Similarity: Belongs to the peptidase S8 family. Furin subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Ubiquitous endoprotease within constitutive secretory pathways capable of cleavage at the RX(K/R)R consensus motif (PubMed:11799113, PubMed:1629222, PubMed:1713771, PubMed:2251280, PubMed:24666235, PubMed:25974265, PubMed:7592877, PubMed:7690548, PubMed:9130696). Mediates processing of TGFB1, an essential step in TGF-beta-1 activation (PubMed:7737999). Converts through proteolytic cleavage the non-functional Brain natriuretic factor prohormone into its active hormone BNP(1-32) (PubMed:20489134, PubMed:21763278). {ECO:0000269\|PubMed:11799113, ECO:0000269\|PubMed:1629222, ECO:0000269\|PubMed:1713771, ECO:0000269\|PubMed:20489134, ECO:0000269\|PubMed:21763278, ECO:0000269\|PubMed:2251280, ECO:0000269\|PubMed:24666235, ECO:0000269\|PubMed:25974265, ECO:0000269\|PubMed:7592877, ECO:0000269\|PubMed:7690548, ECO:0000269\|PubMed:7737999, ECO:0000269\|PubMed:9130696}.



Function:		(Microbial infection) Cleaves and activates diphtheria toxin DT. {ECO:0000269\|PubMed:8253774}.



Function:		(Microbial infection) Cleaves and activates anthrax toxin protective antigen (PA). {ECO:0000269\|PubMed:1438214, ECO:0000269\|PubMed:1644824}.



Function:		(Microbial infection) Required for H7N1 and H5N1 influenza virus infection probably by cleaving hemagglutinin. {ECO:0000269\|PubMed:25974265}.



Function:		(Microbial infection) Able to cleave S.pneumoniae serine-rich repeat protein PsrP. {ECO:0000269\|PubMed:27582320}.



Function:		(Microbial infection) Facilitates human coronaviruses EMC and SARS-CoV-2 infections by proteolytically cleaving the spike protein at the monobasic S1/S2 cleavage site. This cleavage is essential for spike protein-mediated cell-cell fusion and entry into human lung cells. {ECO:0000269\|PubMed:32362314}.


Catalytic activity:		Reaction=Release of mature proteins from their proproteins by cleavage of -Arg-Xaa-Yaa-Arg-\|-Zaa- bonds, where Xaa can be any amino acid and Yaa is Arg or Lys. Releases albumin, complement component C3 and von Willebrand factor from their respective precursors.; EC=3.4.21.75; Evidence={ECO:0000269\|PubMed:11799113, ECO:0000269\|PubMed:1438214, ECO:0000269\|PubMed:1629222, ECO:0000269\|PubMed:1644824, ECO:0000269\|PubMed:1713771, ECO:0000269\|PubMed:2251280, ECO:0000269\|PubMed:24666235, ECO:0000269\|PubMed:25974265, ECO:0000269\|PubMed:32362314, ECO:0000269\|PubMed:7592877, ECO:0000269\|PubMed:7690548, ECO:0000269\|PubMed:7737999, ECO:0000269\|PubMed:8253774, ECO:0000269\|PubMed:9130696};
Cofactor:		Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000269\|PubMed:1644824, ECO:0000269\|PubMed:24666235, ECO:0000269\|PubMed:25974265, ECO:0000269\|PubMed:9130696}; Note=Binds 3 calcium ions per subunit. {ECO:0000269\|PubMed:24666235, ECO:0000269\|PubMed:25974265, ECO:0000269\|PubMed:9130696};
Activity regulation:		Inhibited by the not secondly cleaved propeptide (PubMed:9130696, PubMed:11799113). Inhibited by m-guanidinomethyl- phenylacetyl-Arg-Val-Arg-(amidomethyl)-benzamidine (m-guanidinomethyl- Phac-RVR-Amb) and 4-guanidinomethyl-phenylacetyl-Arg-Tle-Arg-4- amidinobenzylamide (MI-1148) (PubMed:24666235, PubMed:25974265). Inhibited by Decanoyl-Arg-Val-Lys-Arg-chloromethylketone (decanoyl- RVKR-CMK) (PubMed:32362314). {ECO:0000269\|PubMed:11799113, ECO:0000269\|PubMed:24666235, ECO:0000269\|PubMed:25974265, ECO:0000269\|PubMed:32362314, ECO:0000269\|PubMed:9130696}.
Biophysicochemical properties:		pH dependence: Optimum pH is 6.0. {ECO:0000269\|PubMed:9130696};
Subunit:		Interacts with FLNA (By similarity). Binds to PACS1 which mediates TGN localization and connection to clathrin adapters (PubMed:11331585). {ECO:0000250\|UniProtKB:P23188, ECO:0000269\|PubMed:11331585}.
Subcellular location:		Golgi apparatus, trans-Golgi network membrane {ECO:0000269\|PubMed:11331585, ECO:0000269\|PubMed:11799113, ECO:0000269\|PubMed:8846780, ECO:0000269\|PubMed:9130696, ECO:0000269\|PubMed:9412467}; Single-pass type I membrane protein {ECO:0000305}. Cell membrane {ECO:0000269\|PubMed:11799113, ECO:0000269\|PubMed:9130696, ECO:0000269\|PubMed:9412467}; Single-pass type I membrane protein {ECO:0000305}. Secreted {ECO:0000305\|PubMed:11799113}. Endosome membrane {ECO:0000269\|PubMed:9412467}; Single-pass type I membrane protein {ECO:0000305}. Note=Shuttles between the trans-Golgi network and the cell surface (PubMed:9412467, PubMed:11799113). Propeptide cleavage is a prerequisite for exit of furin molecules out of the endoplasmic reticulum (ER). A second cleavage within the propeptide occurs in the trans Golgi network (TGN), followed by the release of the propeptide and the activation of furin (PubMed:11799113). {ECO:0000269\|PubMed:11799113, ECO:0000269\|PubMed:9412467}.
Tissue specificity:		Seems to be expressed ubiquitously. {ECO:0000269\|PubMed:1713771}.
Domain:		Contains a cytoplasmic domain responsible for its TGN localization and recycling from the cell surface. {ECO:0000269\|PubMed:8846780}.
Ptm:		The inhibition peptide, which plays the role of an intramolecular chaperone, is autocatalytically removed in the endoplasmic reticulum (ER) and remains non-covalently bound to furin as a potent autoinhibitor. Following transport to the trans Golgi, a second cleavage within the inhibition propeptide results in propeptide dissociation and furin activation. {ECO:0000269\|PubMed:1629222, ECO:0000269\|PubMed:9130696}.
Ptm:		Phosphorylation is required for TGN localization of the endoprotease. In vivo, exists as di-, mono- and non-phosphorylated forms. {ECO:0000269\|PubMed:8846780}.
Similarity:		Belongs to the peptidase S8 family. Furin subfamily. {ECO:0000305}.