Reviewed, UniProtKB/Swiss-Prot P09958 (FURIN_HUMAN)

Names and origin

Protein names

Recommended name:
    Furin
    EC=3.4.21.75
Alternative name(s):
    Paired basic amino acid residue cleaving enzyme
      Short name=PACE
    Dibasic-processing enzyme

Gene names

Name:	FURIN
Synonyms:	FUR, PACE, PCSK3

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	794 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Furin is likely to represent the ubiquitous endoprotease activity within constitutive secretory pathways and capable of cleavage at the RX(K/R)R consensus motif. Ref.7
Catalytic activity	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 vWF from their respective precursors.
Cofactor	Calcium.
Enzyme regulation	Could be inhibited by the not secondly cleaved propeptide.
Subunit structure	Interacts with FLNA By similarity. Binds to PACS1 which mediates TGN localization and connection to clathrin adapters.
Subcellular location	Golgi apparatus › trans-Golgi network membrane; Single-pass type I membrane protein. Cell membrane; Single-pass type I membrane protein. Note: Shuttles between the trans-Golgi network and the cell surface. 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.
Tissue specificity	Seems to be expressed ubiquitously.
Domain	Contains a cytoplasmic domain responsible for its TGN localization and recycling from the cell surface. Ref.10
Post-translational modification	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. Phosphorylation is required for TGN localization of the endoprotease. In vivo, exists as di-, mono- and non-phosphorylated forms. Ref.11
Sequence similarities	Belongs to the peptidase S8 family. Furin subfamily. Contains 1 homo B/P domain.

Ontologies

Keywords
Cellular component	Cell membrane Golgi apparatus Membrane
Coding sequence diversity	Polymorphism
Domain	Signal Transmembrane
Ligand	Calcium Metal-binding
Molecular function	Hydrolase Protease Serine protease
PTM	Autocatalytic cleavage Cleavage on pair of basic residues Disulfide bond Glycoprotein Phosphoprotein Zymogen
Gene Ontology (GO)
Uncategorized	furin activity Inferred from direct assay. Source: UniProtKB proprotein convertase activity Inferred from direct assay. Source: UniProtKB
Biological process	cell proliferation Inferred from mutant phenotype. Source: UniProtKB negative regulation of low-density lipoprotein receptor catabolic process Inferred from direct assay. Source: HGNC negative regulation of transforming growth factor-beta1 production Inferred from mutant phenotype. Source: UniProtKB nerve growth factor processing Inferred from Experiment. Source: Reactome nerve growth factor production Inferred from direct assay. Source: UniProtKB peptide biosynthetic process Inferred from direct assay. Source: UniProtKB positive regulation of membrane protein ectodomain proteolysis Inferred by curator. Source: UniProtKB proteolysis Inferred from electronic annotation. Source: InterPro regulation of endopeptidase activity Inferred from direct assay. Source: UniProtKB secretion by cell Inferred from direct assay. Source: UniProtKB signal peptide processing Inferred from direct assay. Source: HGNC viral assembly, maturation, egress, and release Inferred from expression pattern. Source: UniProtKB
Cellular component	Golgi membrane Inferred from Experiment. Source: Reactome cell surface Inferred from direct assay. Source: UniProtKB integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW membrane raft Inferred from direct assay. Source: UniProtKB plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell trans-Golgi network Inferred from direct assay. Source: UniProtKB trans-Golgi network transport vesicle Inferred from direct assay. Source: MGI
Molecular function	calcium ion binding Inferred from electronic annotation. Source: UniProtKB-KW nerve growth factor binding Inferred from direct assay. Source: UniProtKB peptide binding Inferred from direct assay. Source: UniProtKB protease binding Inferred from physical interaction. Source: UniProtKB serine-type endopeptidase activity Inferred from electronic annotation. Source: InterPro serine-type endopeptidase inhibitor activity Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 24	24	Potential
	Propeptide	25 – 107	83	Inhibition peptide		PRO_0000027028
	Chain	108 – 794	687	Furin		PRO_0000027029
Regions
	Transmembrane	716 – 738	23	Potential
	Region	759 – 762	4	Cell surface signal
	Motif	498 – 500	3	Cell attachment site Potential
	Motif	773 – 779	7	Trans Golgi network signal
	Compositional bias	556 – 705	150	Cys-rich
Sites
	Active site	153	1	Charge relay system By similarity
	Active site	194	1	Charge relay system By similarity
	Active site	368	1	Charge relay system By similarity
	Metal binding	115	1	Calcium 1 By similarity
	Metal binding	162	1	Calcium 1 By similarity
	Metal binding	208	1	Calcium 1 By similarity
	Metal binding	258	1	Calcium 2 By similarity
	Metal binding	301	1	Calcium 2 By similarity
	Metal binding	331	1	Calcium 2 By similarity
	Site	75 – 76	2	Cleavage, second; by autolysis
	Site	107 – 108	2	Cleavage, first; by autolysis
Amino acid modifications
	Modified residue	773	1	Phosphoserine; by CK2 Ref.11
	Modified residue	775	1	Phosphoserine; by CK2 Ref.11
	Glycosylation	387	1	N-linked (GlcNAc...) Potential
	Glycosylation	440	1	N-linked (GlcNAc...) Potential
	Glycosylation	553	1	N-linked (GlcNAc...) Potential
	Disulfide bond	211 ↔ 360		By similarity
	Disulfide bond	303 ↔ 333		By similarity
	Disulfide bond	450 ↔ 474		By similarity
Natural variations
	Natural variant	43	1	A → V: dbSNP rs16944971.		VAR_051821
	Natural variant	547	1	W → R in cell line LoVo; does not undergo autocatalytic activation and is not transported to the Golgi apparatus.		VAR_055343

Sequences

	Sequence		Length	Mass (Da)
	P09958-1 [UniParc]. Last modified April 1, 1990. Version 2. Checksum: 10C44DD5892EF85D	FASTA	794	86,678
	10 20 30 40 50 60 MELRPWLLWV VAATGTLVLL AADAQGQKVF TNTWAVRIPG GPAVANSVAR KHGFLNLGQI 70 80 90 100 110 120 FGDYYHFWHR GVTKRSLSPH RPRHSRLQRE PQVQWLEQQV AKRRTKRDVY QEPTDPKFPQ 130 140 150 160 170 180 QWYLSGVTQR DLNVKAAWAQ GYTGHGIVVS ILDDGIEKNH PDLAGNYDPG ASFDVNDQDP 190 200 210 220 230 240 DPQPRYTQMN DNRHGTRCAG EVAAVANNGV CGVGVAYNAR IGGVRMLDGE VTDAVEARSL 250 260 270 280 290 300 GLNPNHIHIY SASWGPEDDG KTVDGPARLA EEAFFRGVSQ GRGGLGSIFV WASGNGGREH 310 320 330 340 350 360 DSCNCDGYTN SIYTLSISSA TQFGNVPWYS EACSSTLATT YSSGNQNEKQ IVTTDLRQKC 370 380 390 400 410 420 TESHTGTSAS APLAAGIIAL TLEANKNLTW RDMQHLVVQT SKPAHLNAND WATNGVGRKV 430 440 450 460 470 480 SHSYGYGLLD AGAMVALAQN WTTVAPQRKC IIDILTEPKD IGKRLEVRKT VTACLGEPNH 490 500 510 520 530 540 ITRLEHAQAR LTLSYNRRGD LAIHLVSPMG TRSTLLAARP HDYSADGFND WAFMTTHSWD 550 560 570 580 590 600 EDPSGEWVLE IENTSEANNY GTLTKFTLVL YGTAPEGLPV PPESSGCKTL TSSQACVVCE 610 620 630 640 650 660 EGFSLHQKSC VQHCPPGFAP QVLDTHYSTE NDVETIRASV CAPCHASCAT CQGPALTDCL 670 680 690 700 710 720 SCPSHASLDP VEQTCSRQSQ SSRESPPQQQ PPRLPPEVEA GQRLRAGLLP SHLPEVVAGL 730 740 750 760 770 780 SCAFIVLVFV TVFLVLQLRS GFSFRGVKVY TMDRGLISYK GLPPEAWQEE CPSDSEEDEG 790 RGERTAFIKD QSAL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Structural homology between the human fur gene product and the subtilisin-like protease encoded by yeast KEX2." van den Ouweland A.M.W., van Duijnhoven H.L.P., Keizer G.D., Dorssers L.C.J., van de Ven W.J.M. Nucleic Acids Res. 18:664-664(1990) [PubMed: 2408021] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Blood.
[2]	"Expression of a human proprotein processing enzyme: correct cleavage of the von Willebrand factor precursor at a paired basic amino acid site." Wise R.J., Barr P.J., Wong P.A., Kiefer M.C., Brake A.J., Kaufman R.J. Proc. Natl. Acad. Sci. U.S.A. 87:9378-9382(1990) [PubMed: 2251280] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"cDNA and gene structure for a human subtilisin-like protease with cleavage specificity for paired basic amino acid residues." Barr P.J., Mason O.B., Landsberg K.E., Wong P.A., Kiefer M.C., Brake A.J. DNA Cell Biol. 10:319-328(1991) [PubMed: 1713771] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Lung.
[5]	"Nucleotide sequence analysis of the human fur gene." Van den Ouweland A.M.W., van Groningen J.J.M., Roebrock A.J.M., Onnekink C., Van de Ven W.J.M. Nucleic Acids Res. 17:7101-7102(1989) [PubMed: 2674906] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-280.
[6]	"Evolutionary conserved close linkage of the c-fes/fps proto-oncogene and genetic sequences encoding a receptor-like protein." Roebroek A.J.M., Schalken J.A., Leunissen J.A.M., Onnekink C., Bloemers H.P.J., van de Ven W.J.M. EMBO J. 5:2197-2202(1986) [PubMed: 3023061] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 296-794.
[7]	"A mutation of furin causes the lack of precursor-processing activity in human colon carcinoma LoVo cells." Takahashi S., Kasai K., Hatsuzawa K., Kitamura N., Misumi Y., Ikehara Y., Murakami K., Nakayama K. Biochem. Biophys. Res. Commun. 195:1019-1026(1993) [PubMed: 7690548] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 402-428, FUNCTION. Tissue: Colon carcinoma.
[8]	"A second mutant allele of furin in the processing-incompetent cell line, LoVo. Evidence for involvement of the homo B domain in autocatalytic activation." Takahashi S., Nakagawa T., Kasai K., Banno T., Duguay S.J., Van de Ven W.J.M., Murakami K., Nakayama K. J. Biol. Chem. 270:26565-26569(1995) [PubMed: 7592877] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 527-553, VARIANT ARG-547. Tissue: Colon carcinoma.
[9]	"Activation of human furin precursor processing endoprotease occurs by an intramolecular autoproteolytic cleavage." Leduc R., Molloy S.S., Thorne B.A., Thomas G. J. Biol. Chem. 267:14304-14308(1992) [PubMed: 1629222] [Abstract] Cited for: PROTEOLYTIC PROCESSING.
[10]	"Homology modelling of the catalytic domain of human furin. A model for the eukaryotic subtilisin-like proprotein convertases." Siezen R.J., Creemers J.W.M., van de Ven W.J.M. Eur. J. Biochem. 222:255-266(1994) [PubMed: 8020465] [Abstract] Cited for: 3D-STRUCTURE MODELING OF CATALYTIC DOMAIN.
[11]	"Intracellular trafficking of furin is modulated by the phosphorylation state of a casein kinase II site in its cytoplasmic tail." Jones B.G., Thomas L., Molloy S.S., Thulin C.D., Fry M.D., Walsh K.A., Thomas G. EMBO J. 14:5869-5883(1995) [PubMed: 8846780] [Abstract] Cited for: PHOSPHORYLATION AT SER-773 AND SER-775.
[12]	"PACS-1 binding to adaptors is required for acidic cluster motif-mediated protein traffic." Crump C.M., Xiang Y., Thomas L., Gu F., Austin C., Tooze S.A., Thomas G. EMBO J. 20:2191-2201(2001) [PubMed: 11331585] [Abstract] Cited for: INTERACTION WITH PACS1.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	X17094 mRNA. Translation: CAA34948.1. BC012181 mRNA. Translation: AAH12181.1. X15723 Genomic DNA. Translation: CAA33745.1. X04329 Genomic DNA. Translation: CAA27860.1.
IPI	IPI00018387.
PIR	KXHUF. A39552.
RefSeq	NP_002560.1.
UniGene	Hs.513153
3D structure databases
HSSP	HSSP built from PDB template 1P8J based on UniProtKB P23188.
SMR	P09958. Positions 109-578.
ModBase	Search...
Protein-protein interaction databases
IntAct	P09958. 1 interaction.
Protein family/group databases
MEROPS	S08.071.
PTM databases
PhosphoSite	P09958.
2-D gel databases
OGP	P09958.
Proteomic databases
PeptideAtlas	P09958.
PRIDE	P09958.
Genome annotation databases
Ensembl	ENSG00000140564. Homo sapiens. [Contig view]
GeneID	5045.
KEGG	hsa:5045.
Organism-specific databases
GeneCards	GC15P089212.
H-InvDB	HIX0012578.
HGNC	HGNC:8568. FURIN.
HPA	CAB009499.
MIM	136950. gene.
PharmGKB	PA32894.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	P09958.
HOVERGEN	P09958.
OMA	P09958. PRHSRLQ.
Enzyme and pathway databases
BRENDA	3.4.21.75. 247.
Pathway_Interaction_DB	glypican_3pathway. Glypican 3 network. hif1_tfpathway. HIF-1-alpha transcription factor network. p75ntrpathway. p75(NTR)-mediated signaling.
Reactome	REACT_1069. Post-translational protein modification. REACT_11061. Signalling by NGF. REACT_299. Signaling by Notch. REACT_6844. Signaling by TGF beta.
Gene expression databases
ArrayExpress	P09958.
Bgee	P09958.
CleanEx	HS_FURIN.
GermOnline	ENSG00000140564. Homo sapiens.
Family and domain databases
InterPro	IPR006212. Furin_repeat. IPR000209. Pept_S8_S53. IPR015500. Peptidase_S8_subtilisin-rel. IPR002884. PrprotnconvertsP. [Graphical view]
Gene3D	G3DSA:3.40.50.200. Pept_S8_S53. 1 hit.
PANTHER	PTHR10795. SubtilSerProt. 1 hit.
Pfam	PF01483. P_proprotein. 1 hit. PF00082. Peptidase_S8. 1 hit. [Graphical view]
PRINTS	PR00723. SUBTILISIN.
ProDom	PD000717. PrprotnconvertsP. 1 hit. [Graphical view] [Entries sharing at least one domain]
SMART	SM00261. FU. 2 hits. [Graphical view]
PROSITE	PS00136. SUBTILASE_ASP. 1 hit. PS00137. SUBTILASE_HIS. 1 hit. PS00138. SUBTILASE_SER. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	19422.
PMAP-CutDB	P09958.
SOURCE	Search...

Entry information

Entry name

FURIN_HUMAN

Accession

Primary (citable) accession number: P09958
Secondary accession number(s): Q14336, Q6LBS3, Q9UCZ5

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1989
Last sequence update:	April 1, 1990
Last modified:	June 16, 2009
This is version 120 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)