| IED ID | IndEnz0005000446 |
| Enzyme Type ID | lipase000446 |
| Protein Name |
Furin EC 3.4.21.75 Dibasic-processing enzyme Paired basic amino acid residue-cleaving enzyme PACE |
| Gene Name | FURIN FUR PACE PCSK3 |
| Organism | Homo sapiens (Human) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MELRPWLLWVVAATGTLVLLAADAQGQKVFTNTWAVRIPGGPAVANSVARKHGFLNLGQIFGDYYHFWHRGVTKRSLSPHRPRHSRLQREPQVQWLEQQVAKRRTKRDVYQEPTDPKFPQQWYLSGVTQRDLNVKAAWAQGYTGHGIVVSILDDGIEKNHPDLAGNYDPGASFDVNDQDPDPQPRYTQMNDNRHGTRCAGEVAAVANNGVCGVGVAYNARIGGVRMLDGEVTDAVEARSLGLNPNHIHIYSASWGPEDDGKTVDGPARLAEEAFFRGVSQGRGGLGSIFVWASGNGGREHDSCNCDGYTNSIYTLSISSATQFGNVPWYSEACSSTLATTYSSGNQNEKQIVTTDLRQKCTESHTGTSASAPLAAGIIALTLEANKNLTWRDMQHLVVQTSKPAHLNANDWATNGVGRKVSHSYGYGLLDAGAMVALAQNWTTVAPQRKCIIDILTEPKDIGKRLEVRKTVTACLGEPNHITRLEHAQARLTLSYNRRGDLAIHLVSPMGTRSTLLAARPHDYSADGFNDWAFMTTHSWDEDPSGEWVLEIENTSEANNYGTLTKFTLVLYGTAPEGLPVPPESSGCKTLTSSQACVVCEEGFSLHQKSCVQHCPPGFAPQVLDTHYSTENDVETIRASVCAPCHASCATCQGPALTDCLSCPSHASLDPVEQTCSRQSQSSRESPPQQQPPRLPPEVEAGQRLRAGLLPSHLPEVVAGLSCAFIVLVFVTVFLVLQLRSGFSFRGVKVYTMDRGLISYKGLPPEAWQEECPSDSEEDEGRGERTAFIKDQSAL |
| Enzyme Length | 794 |
| Uniprot Accession Number | P09958 |
| Absorption | |
| Active Site | ACT_SITE 153; /note=Charge relay system; /evidence=ECO:0000255|PROSITE-ProRule:PRU01240; ACT_SITE 194; /note=Charge relay system; /evidence=ECO:0000255|PROSITE-ProRule:PRU01240; ACT_SITE 368; /note=Charge relay system; /evidence=ECO:0000255|PROSITE-ProRule:PRU01240 |
| Activity Regulation | 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). Inhibited by heparin/heparan sulfate-binding (PubMed:2408021). {ECO:0000269|PubMed:11799113, ECO:0000269|PubMed:2408021, ECO:0000269|PubMed:24666235, ECO:0000269|PubMed:25974265, ECO:0000269|PubMed:32362314, ECO:0000269|PubMed:9130696}. |
| Binding Site | BINDING 154; /note="Substrate"; /evidence="ECO:0000305|PubMed:24666235, ECO:0000305|PubMed:25974265, ECO:0007744|PDB:4OMC, ECO:0007744|PDB:4OMD, ECO:0007744|PDB:4RYD"; BINDING 236; /note="Substrate"; /evidence="ECO:0000305|PubMed:24666235, ECO:0000305|PubMed:25974265, ECO:0007744|PDB:4OMC, ECO:0007744|PDB:4OMD, ECO:0007744|PDB:4RYD"; BINDING 264; /note="Substrate"; /evidence="ECO:0000305|PubMed:24666235, ECO:0000305|PubMed:25974265, ECO:0007744|PDB:4OMC, ECO:0007744|PDB:4OMD, ECO:0007744|PDB:4RYD"; BINDING 306; /note="Substrate"; /evidence="ECO:0000305|PubMed:24666235, ECO:0000305|PubMed:25974265, ECO:0007744|PDB:4OMC, ECO:0007744|PDB:4OMD, ECO:0007744|PDB:4RYD"; BINDING 308; /note="Substrate"; /evidence="ECO:0000305|PubMed:24666235, ECO:0000305|PubMed:25974265, ECO:0007744|PDB:4OMC, ECO:0007744|PDB:4OMD, ECO:0007744|PDB:4RYD"; BINDING 368; /note="Substrate"; /evidence="ECO:0000305|PubMed:24666235, ECO:0000305|PubMed:25974265, ECO:0007744|PDB:4OMC, ECO:0007744|PDB:4OMD, ECO:0007744|PDB:4RYD" |
| Calcium Binding | |
| catalytic Activity | 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}; |
| DNA Binding | |
| EC Number | 3.4.21.75 |
| Enzyme Function | 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). By mediating processing of accessory subunit ATP6AP1/Ac45 of the V-ATPase, regulates the acidification of dense-core secretory granules in islets of Langerhans cells (By similarity). {ECO:0000250|UniProtKB:P23188, 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}.; FUNCTION: (Microbial infection) Facilitates mumps virus infection by proteolytically cleaving the viral fusion protein F. {ECO:0000269|PubMed:32295904}. |
| Temperature Dependency | |
| PH Dependency | BIOPHYSICOCHEMICAL PROPERTIES: pH dependence: Optimum pH is 6.0. {ECO:0000269|PubMed:9130696}; |
| Pathway | |
| nucleotide Binding | |
| Features | Active site (3); Beta strand (23); Binding site (6); Chain (1); Compositional bias (1); Disulfide bond (3); Domain (2); Glycosylation (3); Helix (17); Metal binding (12); Modified residue (2); Motif (2); Mutagenesis (6); Natural variant (5); Propeptide (1); Region (7); Repeat (2); Signal peptide (1); Site (2); Topological domain (2); Transmembrane (1); Turn (10) |
| Keywords | 3D-structure;Autocatalytic cleavage;Calcium;Cell membrane;Cleavage on pair of basic residues;Disulfide bond;Endosome;Glycoprotein;Golgi apparatus;Heparin-binding;Host-virus interaction;Hydrolase;Membrane;Metal-binding;Phosphoprotein;Protease;Reference proteome;Repeat;Secreted;Serine protease;Signal;Transmembrane;Transmembrane helix;Zymogen |
| Interact With | P05067; P50281; Q9H239; O14793; K9N5Q8; P0DTC2; Q91QT1 |
| Induction | |
| Subcellular Location | 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}. |
| Modified Residue | MOD_RES 773; /note=Phosphoserine; by CK2; /evidence=ECO:0000269|PubMed:8846780; MOD_RES 775; /note=Phosphoserine; by CK2; /evidence=ECO:0000269|PubMed:8846780 |
| Post Translational Modification | 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}. |
| Signal Peptide | SIGNAL 1..26; /evidence=ECO:0000255 |
| Structure 3D | X-ray crystallography (29); NMR spectroscopy (1) |
| Cross Reference PDB | 4OMC; 4OMD; 4RYD; 4Z2A; 5JMO; 5JXG; 5JXH; 5JXI; 5JXJ; 5MIM; 6A8Y; 6EQV; 6EQW; 6EQX; 6HLB; 6HLD; 6HLE; 6HZA; 6HZB; 6HZC; 6HZD; 6YD2; 6YD3; 6YD4; 6YD7; 7O1U; 7O1W; 7O1Y; 7O20; 7O22; |
| Mapped Pubmed ID | 10075724; 10198291; 10508235; 10669757; 10900462; 10935626; 10956649; 11071887; 11141505; 11294867; 11323410; 11380615; 11390472; 11416205; 11422372; 11571266; 11723118; 11804956; 11830519; 11861638; 11927537; 12049766; 12220680; 12411321; 12447384; 12482908; 12547702; 12584323; 12586364; 12670890; 12736257; 12755693; 14596804; 14623079; 14644155; 14739277; 14741044; 14744861; 15207811; 15240540; 15247425; 15371436; 15474033; 15527779; 15564468; 15584904; 15596135; 15606899; 15611046; 15637056; 15659365; 15803139; 15911696; 16061697; 16109723; 1639841; 16407210; 16627761; 16648485; 16912035; 16942750; 16977309; 17088546; 17234158; 17283058; 17353931; 17360815; 17477394; 17627939; 17641413; 17905608; 17905609; 17909005; 17938254; 17948127; 18037384; 18064302; 18174282; 18245819; 18323532; 18467449; 18544638; 18546152; 18772886; 18826955; 19056739; 19152512; 19193799; 19477160; 19492430; 19541935; 19701457; 19913121; 19998449; 20062797; 20101215; 20581395; 20605791; 20608975; 20628086; 20634490; 20635860; 20707915; 20811902; 20945401; 21068237; 21114864; 21147780; 21296375; 21325420; 21406565; 21503879; 21550985; 21880759; 21889147; 21988832; 22038627; 22246777; 22246778; 22247010; 22479394; 22577343; 22808247; 23065687; 23135270; 23302673; 23390091; 23558288; 23568742; 23598405; 23653353; 23661674; 23686857; 23744066; 23829672; 23835774; 23936445; 24257604; 24397894; 24436242; 24454770; 25026302; 25175744; 25355923; 25540379; 25543063; 25552509; 25795784; 25813623; 25933376; 26137475; 26283728; 26346780; 26488448; 26496610; 26569287; 26933753; 26934567; 26934667; 27548722; 27572312; 27647913; 27670069; 27760099; 27798871; 28013223; 28259973; 28369813; 28402100; 28484053; 29265076; 29314830; 29465367; 29499969; 29976768; 30021905; 30135209; 30333479; 30680958; 30706700; 31091448; 31253944; 31505793; 31936902; 32060422; 32067586; 32139876; 32329629; 32512290; 32532959; 32660959; 32691890; 32703818; 32730764; 32840921; 32873908; 32920451; 33243086; 33413387; 33476708; 33493182; 33732412; 33910372; 34155192; 34356057; 34415722; 34579647; 34856891; 7721880; 7746327; 8163529; 8473289; 8546712; 8615794; 8621565; 8645182; 8804434; 9244302; 9642263; 9653148; 9727485; 9885250; |
| Motif | MOTIF 498..500; /note=Cell attachment site; /evidence=ECO:0000255; MOTIF 773..779; /note=Trans Golgi network signal; /evidence=ECO:0000269|PubMed:8846780 |
| Gene Encoded By | |
| Mass | 86,678 |
| Kinetics | |
| Metal Binding | METAL 115; /note="Calcium 1"; /evidence="ECO:0000269|PubMed:24666235, ECO:0000269|PubMed:25974265, ECO:0007744|PDB:4OMC, ECO:0007744|PDB:4OMD, ECO:0007744|PDB:4RYD"; METAL 162; /note="Calcium 1"; /evidence="ECO:0000269|PubMed:24666235, ECO:0000269|PubMed:25974265, ECO:0007744|PDB:4OMC, ECO:0007744|PDB:4OMD, ECO:0007744|PDB:4RYD"; METAL 174; /note="Calcium 2"; /evidence="ECO:0000269|PubMed:24666235, ECO:0000269|PubMed:25974265, ECO:0007744|PDB:4OMC, ECO:0007744|PDB:4OMD, ECO:0007744|PDB:4RYD"; METAL 179; /note="Calcium 2"; /evidence="ECO:0000269|PubMed:24666235, ECO:0000269|PubMed:25974265, ECO:0007744|PDB:4OMC, ECO:0007744|PDB:4OMD, ECO:0007744|PDB:4RYD"; METAL 181; /note="Calcium 2; via carbonyl oxygen"; /evidence="ECO:0000269|PubMed:24666235, ECO:0000269|PubMed:25974265, ECO:0007744|PDB:4OMC, ECO:0007744|PDB:4OMD, ECO:0007744|PDB:4RYD"; METAL 205; /note="Calcium 1; via carbonyl oxygen"; /evidence="ECO:0000269|PubMed:24666235, ECO:0000269|PubMed:25974265, ECO:0007744|PDB:4OMC, ECO:0007744|PDB:4OMD, ECO:0007744|PDB:4RYD"; METAL 208; /note="Calcium 1"; /evidence="ECO:0000269|PubMed:24666235, ECO:0000269|PubMed:25974265, ECO:0007744|PDB:4OMC, ECO:0007744|PDB:4OMD, ECO:0007744|PDB:4RYD"; METAL 210; /note="Calcium 1; via carbonyl oxygen"; /evidence="ECO:0000269|PubMed:24666235, ECO:0000269|PubMed:25974265, ECO:0007744|PDB:4OMC, ECO:0007744|PDB:4OMD, ECO:0007744|PDB:4RYD"; METAL 212; /note="Calcium 1; via carbonyl oxygen"; /evidence="ECO:0000269|PubMed:24666235, ECO:0000269|PubMed:25974265, ECO:0007744|PDB:4OMC, ECO:0007744|PDB:4OMD, ECO:0007744|PDB:4RYD"; METAL 258; /note="Calcium 3"; /evidence="ECO:0000269|PubMed:24666235, ECO:0000269|PubMed:25974265, ECO:0007744|PDB:4OMC, ECO:0007744|PDB:4OMD, ECO:0007744|PDB:4RYD"; METAL 301; /note="Calcium 3"; /evidence="ECO:0000269|PubMed:24666235, ECO:0000269|PubMed:25974265, ECO:0007744|PDB:4OMC, ECO:0007744|PDB:4OMD, ECO:0007744|PDB:4RYD"; METAL 331; /note="Calcium 3"; /evidence="ECO:0000269|PubMed:24666235, ECO:0000269|PubMed:25974265, ECO:0007744|PDB:4OMC, ECO:0007744|PDB:4OMD, ECO:0007744|PDB:4RYD" |
| Rhea ID | |
| Cross Reference Brenda | 3.4.21.75; |