FURIN_BOVIN
ID FURIN_BOVIN Reviewed; 797 AA.
AC Q28193;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1997, sequence version 1.
DT 03-AUG-2022, entry version 166.
DE RecName: Full=Furin;
DE EC=3.4.21.75 {ECO:0000269|PubMed:7806563};
DE AltName: Full=Dibasic-processing enzyme;
DE AltName: Full=Paired basic amino acid residue-cleaving enzyme;
DE Short=PACE;
DE AltName: Full=Trans Golgi network protease furin;
DE Flags: Precursor;
GN Name=FURIN; Synonyms=FUR, PACE;
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, COFACTOR,
RP SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, AND GLYCOSYLATION.
RC TISSUE=Kidney;
RX PubMed=7806563; DOI=10.1083/jcb.127.6.1829;
RA Vey M., Schaefer W., Berghoefer S., Klenk H., Garten W.;
RT "Maturation of the trans-Golgi network protease furin: compartmentalization
RT of propeptide removal, substrate cleavage, and COOH-terminal truncation.";
RL J. Cell Biol. 127:1829-1842(1994).
CC -!- FUNCTION: Ubiquitous endoprotease within constitutive secretory
CC pathways capable of cleavage at the RX(K/R)R consensus motif
CC (PubMed:7806563). Mediates processing of TGFB1, an essential step in
CC TGF-beta-1 activation (By similarity). By mediating processing of
CC accessory subunit ATP6AP1/Ac45 of the V-ATPase, regulates the
CC acidification of dense-core secretory granules in islets of Langerhans
CC cells (By similarity). {ECO:0000250|UniProtKB:P09958,
CC ECO:0000250|UniProtKB:P23188, ECO:0000269|PubMed:7806563}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Release of mature proteins from their proproteins by cleavage
CC of -Arg-Xaa-Yaa-Arg-|-Zaa- bonds, where Xaa can be any amino acid and
CC Yaa is Arg or Lys. Releases albumin, complement component C3 and von
CC Willebrand factor from their respective precursors.; EC=3.4.21.75;
CC Evidence={ECO:0000269|PubMed:7806563};
CC -!- COFACTOR:
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108;
CC Evidence={ECO:0000269|PubMed:7806563};
CC Note=Binds 3 calcium ions per subunit. {ECO:0000250|UniProtKB:P09958};
CC -!- ACTIVITY REGULATION: Inhibited by the not secondly cleaved propeptide.
CC Inhibited by m-guanidinomethyl-phenylacetyl-Arg-Val-Arg-(amidomethyl)-
CC benzamidine (m-guanidinomethyl-Phac-RVR-Amb) and 4-guanidinomethyl-
CC phenylacetyl-Arg-Tle-Arg-4-amidinobenzylamide (MI-1148). Inhibited by
CC Decanoyl-Arg-Val-Lys-Arg-chloromethylketone (decanoyl-RVKR-CMK).
CC Inhibited by heparin/heparan sulfate-binding.
CC {ECO:0000250|UniProtKB:P09958}.
CC -!- SUBUNIT: Interacts with FLNA. Binds to PACS1 which mediates TGN
CC localization and connection to clathrin adapters.
CC {ECO:0000250|UniProtKB:P09958, ECO:0000250|UniProtKB:P23188}.
CC -!- SUBCELLULAR LOCATION: Golgi apparatus, trans-Golgi network membrane
CC {ECO:0000269|PubMed:7806563}; Single-pass type I membrane protein
CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:7806563}; Single-pass
CC type I membrane protein {ECO:0000305}. Secreted
CC {ECO:0000269|PubMed:7806563}. Endosome membrane
CC {ECO:0000250|UniProtKB:P09958}; Single-pass type I membrane protein
CC {ECO:0000305}. Note=Shuttles between the trans-Golgi network and the
CC cell surface. Propeptide cleavage is a prerequisite for exit of furin
CC molecules out of the endoplasmic reticulum (ER). A second cleavage
CC within the propeptide occurs in the trans Golgi network (TGN), followed
CC by the release of the propeptide and the activation of furin.
CC {ECO:0000269|PubMed:7806563}.
CC -!- DOMAIN: Contains a cytoplasmic domain responsible for its TGN
CC localization and recycling from the cell surface.
CC {ECO:0000250|UniProtKB:P09958}.
CC -!- PTM: The inhibition peptide, which plays the role of an intramolecular
CC chaperone, is autocatalytically removed in the endoplasmic reticulum
CC (ER) and remains non-covalently bound to furin as a potent
CC autoinhibitor. Following transport to the trans Golgi, a second
CC cleavage within the inhibition propeptide results in propeptide
CC dissociation and furin activation. {ECO:0000269|PubMed:7806563}.
CC -!- PTM: Phosphorylation is required for TGN localization of the
CC endoprotease. In vivo, exists as di-, mono- and non-phosphorylated
CC forms. {ECO:0000250|UniProtKB:P09958}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:7806563}.
CC -!- SIMILARITY: Belongs to the peptidase S8 family. Furin subfamily.
CC {ECO:0000305}.
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DR EMBL; X75956; CAA53569.1; -; mRNA.
DR PIR; I46044; I46044.
DR RefSeq; NP_776561.1; NM_174136.2.
DR AlphaFoldDB; Q28193; -.
DR SMR; Q28193; -.
DR ELM; Q28193; -.
DR STRING; 9913.ENSBTAP00000003826; -.
DR MEROPS; S08.071; -.
DR PaxDb; Q28193; -.
DR PRIDE; Q28193; -.
DR GeneID; 281374; -.
DR KEGG; bta:281374; -.
DR CTD; 5045; -.
DR eggNOG; KOG3525; Eukaryota.
DR InParanoid; Q28193; -.
DR OrthoDB; 473018at2759; -.
DR Proteomes; UP000009136; Unplaced.
DR GO; GO:0010008; C:endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:1904399; F:heparan sulfate binding; ISS:UniProtKB.
DR GO; GO:0008201; F:heparin binding; ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004252; F:serine-type endopeptidase activity; ISS:UniProtKB.
DR GO; GO:1901394; P:positive regulation of transforming growth factor beta1 activation; ISS:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR CDD; cd00064; FU; 2.
DR CDD; cd04059; Peptidases_S8_Protein_convertases_Kexins_Furin-like; 1.
DR Gene3D; 3.30.70.850; -; 1.
DR Gene3D; 3.40.50.200; -; 1.
DR InterPro; IPR006212; Furin_repeat.
DR InterPro; IPR008979; Galactose-bd-like_sf.
DR InterPro; IPR009030; Growth_fac_rcpt_cys_sf.
DR InterPro; IPR034182; Kexin/furin.
DR InterPro; IPR002884; P_dom.
DR InterPro; IPR000209; Peptidase_S8/S53_dom.
DR InterPro; IPR036852; Peptidase_S8/S53_dom_sf.
DR InterPro; IPR023827; Peptidase_S8_Asp-AS.
DR InterPro; IPR022398; Peptidase_S8_His-AS.
DR InterPro; IPR015500; Peptidase_S8_subtilisin-rel.
DR InterPro; IPR032815; S8_pro-domain.
DR InterPro; IPR038466; S8_pro-domain_sf.
DR Pfam; PF01483; P_proprotein; 1.
DR Pfam; PF00082; Peptidase_S8; 1.
DR Pfam; PF16470; S8_pro-domain; 1.
DR PRINTS; PR00723; SUBTILISIN.
DR SMART; SM00261; FU; 2.
DR SUPFAM; SSF49785; SSF49785; 1.
DR SUPFAM; SSF52743; SSF52743; 1.
DR SUPFAM; SSF57184; SSF57184; 1.
DR PROSITE; PS51829; P_HOMO_B; 1.
DR PROSITE; PS51892; SUBTILASE; 1.
DR PROSITE; PS00136; SUBTILASE_ASP; 1.
DR PROSITE; PS00137; SUBTILASE_HIS; 1.
PE 1: Evidence at protein level;
KW Autocatalytic cleavage; Calcium; Cell membrane;
KW Cleavage on pair of basic residues; Disulfide bond; Endosome; Glycoprotein;
KW Golgi apparatus; Heparin-binding; Hydrolase; Membrane; Metal-binding;
KW Phosphoprotein; Protease; Reference proteome; Repeat; Secreted;
KW Serine protease; Signal; Transmembrane; Transmembrane helix; Zymogen.
FT SIGNAL 1..26
FT /evidence="ECO:0000255"
FT PROPEP 27..107
FT /note="Inhibition peptide"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT /id="PRO_0000027026"
FT CHAIN 108..797
FT /note="Furin"
FT /id="PRO_0000027027"
FT TOPO_DOM 108..718
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 719..739
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 740..797
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT DOMAIN 121..435
FT /note="Peptidase S8"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT DOMAIN 444..576
FT /note="P/Homo B"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01173"
FT REPEAT 577..620
FT /note="FU 1"
FT /evidence="ECO:0000255"
FT REPEAT 638..681
FT /note="FU 2"
FT /evidence="ECO:0000255"
FT REGION 160..183
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 673..702
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 762..765
FT /note="Cell surface signal"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT REGION 770..797
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 498..500
FT /note="Cell attachment site"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00293"
FT MOTIF 776..782
FT /note="Trans Golgi network signal"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT COMPBIAS 687..701
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 153
FT /note="Charge relay system"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT ACT_SITE 194
FT /note="Charge relay system"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT ACT_SITE 368
FT /note="Charge relay system"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT BINDING 115
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 154
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 162
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 174
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 179
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 181
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 191..192
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 205
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 208
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 210
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 212
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 236
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 253..258
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 258
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 264
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 292..295
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 301
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 306
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 308
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 331
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT BINDING 368
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT SITE 75..76
FT /note="Cleavage, second; by autolysis"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT SITE 107..108
FT /note="Cleavage, first; by autolysis"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT MOD_RES 776
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT MOD_RES 778
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P09958"
FT CARBOHYD 387
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 440
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 553
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 211..360
FT /evidence="ECO:0000250|UniProtKB:P23188"
FT DISULFID 303..333
FT /evidence="ECO:0000250|UniProtKB:P23188"
FT DISULFID 450..474
FT /evidence="ECO:0000250|UniProtKB:P23188"
SQ SEQUENCE 797 AA; 87251 MW; 466F28EC0246C3D2 CRC64;
MELRPWLFWV VAAAGALVLL VADARGEKVF TNTWAVHIPG GPAVADRVAR KHGFLNLGQI
FGDYYHFWHR AVTKRSLSPH RLGHNRLQRE PQVKWLEQQV AKRRAKRDIY QEPTDPKFPQ
QWYLSGVTQR DLNVKEAWAQ GYTGRGIVVS ILDDGIEKNH PDLAGNYDPG ASFDVNDQDP
DPQPRYTQMN DNRHGTRCAG EVAAVANNGV CGVGVAYNAR IGGVRMLDGE VTDAVEARSL
GLNPNHIHIY SASWGPEDDG KTVDGPAHLA EEAFFRGVSQ GRGGLGSIFV WASGNGGREH
DSCNCDGYTN SIYTLSISSA TQFGNVPWYS EACSSTLATT YSSGNQNEKQ IVTTDLRQKC
TESHTGTSAF APLAAGIIAL TLEANKNLTW RDMQHLVVRT SKPAHLNAND WATNGVGRKV
SHSYGYGLLD AGAMVALAQN WTTVAPQRKC TIDILTEPKD IGKRLEVRKT VTACLGEPSH
ITRLEHAQAR LTLSYNRRGD LAIHLVSPMG TRSTLLAARP HDYSADGFND WAFMTTHSWD
EDPSGEWVLE IENTSEANNY GTLTKFTLVL YGTAPEGLPT PPESIGCKTL TSSQACVVCE
EGFSLHQKNC VQHCPPGFAP QVLDTHYSTE NDVEIIRASV CTPCHASCAT CQGPAPTDCL
SCPSHASLDP VEQTCSRQSQ SSRESHQQQP PPPPRPPPAE VATEPRLRAD LLPSHLPEVV
AGLSCAFIVL VFVTVFLVLQ LRSGFSFRGV KVYTMDRGLI SYKGLPPEAW QEECPSDSEE
DEGRGERTAF IKDQSAL
