Furin

"FUR" redirects here. For other uses, see Fur (disambiguation).

Furin (paired basic amino acid cleaving enzyme)
PDB rendering based on 1p8j.
Available structures PDB 1p8j
Identifiers
Symbols	FURIN; FUR; PACE; PCSK3; SPC1
External IDs	OMIM: 136950 MGI: 97513 HomoloGene: 1930 GeneCards: FURIN Gene
EC number	3.4.21.75
Gene Ontology Molecular function • protease binding • endopeptidase activity • serine-type endopeptidase activity • serine-type endopeptidase activity • serine-type endopeptidase inhibitor activity • protein binding • peptidase activity • peptide binding • metal ion binding • nerve growth factor binding Cellular component • Golgi membrane • extracellular space • endoplasmic reticulum membrane • Golgi apparatus • Golgi lumen • trans-Golgi network • plasma membrane • cell surface • integral to membrane • trans-Golgi network transport vesicle • Golgi cisterna • membrane raft Biological process • signal peptide processing • proteolysis • transforming growth factor beta receptor signaling pathway • Notch signaling pathway • aging • cell proliferation • peptide hormone processing • peptidyl-glutamic acid carboxylation • viral assembly, maturation, egress, and release • positive regulation of cell migration • positive regulation of transforming growth factor beta receptor signaling pathway • nerve growth factor processing • negative regulation of low-density lipoprotein particle receptor catabolic process • nerve growth factor production • negative regulation of nerve growth factor production • negative regulation of transforming growth factor-beta1 production • secretion by cell • regulation of protein catabolic process • peptide biosynthetic process • post-translational protein modification • cellular protein metabolic process • nerve growth factor receptor signaling pathway • positive regulation of membrane protein ectodomain proteolysis • protein maturation by peptide bond cleavage • protein maturation by peptide bond cleavage • regulation of endopeptidase activity Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5045	18550
Ensembl	ENSG00000140564	ENSMUSG00000030530
UniProt	P09958	Q6GTN6
RefSeq (mRNA)	NM_002569.2	XM_980423
RefSeq (protein)	NP_002560.1	XP_985517
Location (UCSC)	Chr 15: 91.41 – 91.43 Mb	Chr 7: 87.53 – 87.55 Mb
PubMed search	[1]	[2]

Furin is a protein that in humans is encoded by the FURIN gene.^[1][2][3][4] It was named furin because it was in the upstream region of an oncogene known as FES. The gene was known as FUR (FES Upstream Region) and therefore the protein was named furin. Furin is also known as PACE (Paired basic Amino acid Cleaving Enzyme).

Function

The protein encoded by this gene is an enzyme which belongs to the subtilisin-like proprotein convertase family. The members of this family are proprotein convertases that process latent precursor proteins into their biologically active products. This encoded protein is a calcium-dependent serine endoprotease that can efficiently cleave precursor proteins at their paired basic amino acid processing sites. Some of its substrates are: proparathyroid hormone, transforming growth factor beta 1 precursor, proalbumin, pro-beta-secretase, membrane type-1 matrix metalloproteinase, beta subunit of pro-nerve growth factor and von Willebrand factor. A furin-like pro-protein convertase has been implicated in the processing of RGMc (also called hemojuvelin Hemojuvelin), a gene involved in a severe iron-overload disorder called juvenile hemochromatosis. Both the Ganz and Rotwein groups demonstrated that furin-like proprotein convertases (PPC) are responsible for conversion of 50 kDa HJV to a 40 kDa protein with a truncated COOH-terminus, at a conserved polybasic RNRR site. This suggests a potential mechanism to generate the soluble forms of HJV/hemojuvelin (s-hemojuvelin) found in the blood of rodents and humans.^[5][6]

Furin is also thought to be one of the proteases responsible for the proteolytic cleavage of HIV envelope polyprotein precursor gp160 to gp120 and gp41 prior to viral assembly. This gene is thought to play a role in tumor progression. The use of alternate polyadenylation sites has been found for this gene.^[3]

Furin is enriched in the Golgi apparatus, where it functions to cleave other proteins into their mature/active forms.^[7] Furin cleaves proteins just downstream of a basic amino acid target sequence (canonically, Arg-X-(Arg/Lys) -Arg'). In addition to processing cellular precursor proteins, furin is also utilized by a number of pathogens. For example, the envelope proteins of viruses such as HIV, influenza and dengue fever viruses must be cleaved by furin or furin-like proteases to become fully functional. Anthrax toxin, pseudomonas exotoxin, and papillomaviruses must be processed by furin during their initial entry into host cells. Inhibitors of furin are under consideration as therapeutic agents for treating anthrax infection.^[8]

Expression of furin in T-cells is required for maintenance of peripheral immune tolerance.^[9]

Interactions

Furin has been shown to interact with PACS1.^[10]

References

1. ^ Wise RJ, Barr PJ, Wong PA, Kiefer MC, Brake AJ, Kaufman RJ (Jan 1991). "Expression of a human proprotein processing enzyme: correct cleavage of the von Willebrand factor precursor at a paired basic amino acid site". Proc Natl Acad Sci U S A 87 (23): 9378–82. doi:10.1073/pnas.87.23.9378. PMC 55168. PMID 2251280. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=55168. 
2. ^ Kiefer MC, Tucker JE, Joh R, Landsberg KE, Saltman D, Barr PJ (Jan 1992). "Identification of a second human subtilisin-like protease gene in the fes/fps region of chromosome 15". DNA Cell Biol 10 (10): 757–69. doi:10.1089/dna.1991.10.757. PMID 1741956. 
3. ^ ^{a b} "Entrez Gene: FURIN furin (paired basic amino acid cleaving enzyme)". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5045. 
4. ^ Roebroek AJ, Schalken JA, Leunissen JA, Onnekink C, Bloemers HP, Van de Ven WJ (September 1986). "Evolutionary conserved close linkage of the c-fes/fps proto-oncogene and genetic sequences encoding a receptor-like protein". EMBO J. 5 (9): 2197–202. PMC 1167100. PMID 3023061. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1167100. 
5. ^ Lin L, Nemeth E, Goodnough JB, Thapa DR, Gabayan V, Ganz T (2008). "Soluble hemojuvelin is released by proprotein convertase-mediated cleavage at a conserved polybasic RNRR site". Blood Cells Mol. Dis. 40 (1): 122–31. doi:10.1016/j.bcmd.2007.06.023. PMC 2211380. PMID 17869549. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2211380. 
6. ^ Kuninger D, Kuns-Hashimoto R, Nili M, Rotwein P (2008). "Pro-protein convertases control the maturation and processing of the iron-regulatory protein, RGMc/hemojuvelin". BMC Biochem. 9: 9. doi:10.1186/1471-2091-9-9. PMC 2323002. PMID 18384687. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2323002. 
7. ^ Thomas G (October 2002). "Furin at the cutting edge: from protein traffic to embryogenesis and disease". Nat. Rev. Mol. Cell Biol. 3 (10): 753–66. doi:10.1038/nrm934. PMC 1964754. PMID 12360192. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1964754. 
8. ^ Shiryaev SA, Remacle AG, Ratnikov BI, Nelson NA, Savinov AY, Wei G, Bottini M, Rega MF, Parent A, Desjardins R, Fugere M, Day R, Sabet M, Pellecchia M, Liddington RC, Smith JW, Mustelin T, Guiney DG, Lebl M, Strongin AY (July 2007). "Targeting host cell furin proprotein convertases as a therapeutic strategy against bacterial toxins and viral pathogens". J. Biol. Chem. 282 (29): 20847–53. doi:10.1074/jbc.M703847200. PMID 17537721. 
9. ^ Pesu M, Watford WT, Wei L, Xu L, Fuss I, Strober W, Andersson J, Shevach EM, Quezado M, Bouladoux N, Roebroek A, Belkaid Y, Creemers J, O'Shea JJ (August 2008). "T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance". Nature 455 (7210): 246. doi:10.1038/nature07210. PMC 2758057. PMID 18701887. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2758057. 
10. ^ Wan, L; Molloy S S, Thomas L, Liu G, Xiang Y, Rybak S L, Thomas G (Jul. 1998). "PACS-1 defines a novel gene family of cytosolic sorting proteins required for trans-Golgi network localization". Cell (UNITED STATES) 94 (2): 205–16. doi:10.1016/S0092-8674(00)81420-8. ISSN 0092-8674. PMID 9695949. 

Further reading

• Nakayama K (1998). "Furin: a mammalian subtilisin/Kex2p-like endoprotease involved in processing of a wide variety of precursor proteins.". Biochem. J. 327 ( Pt 3): 625–35. PMC 1218878. PMID 9599222. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1218878. 
• Bassi DE, Mahloogi H, Klein-Szanto AJ (2000). "The proprotein convertases furin and PACE4 play a significant role in tumor progression.". Mol. Carcinog. 28 (2): 63–9. doi:10.1002/1098-2744(200006)28:2<63::AID-MC1>3.0.CO;2-C. PMID 10900462. 
• Hallenberger S, Bosch V, Angliker H, et al. (1992). "Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gp160.". Nature 360 (6402): 358–61. doi:10.1038/360358a0. PMID 1360148. 
• Rehemtulla A, Kaufman RJ (1992). "Preferred sequence requirements for cleavage of pro-von Willebrand factor by propeptide-processing enzymes.". Blood 79 (9): 2349–55. PMID 1571548. 
• Leduc R, Molloy SS, Thorne BA, Thomas G (1992). "Activation of human furin precursor processing endoprotease occurs by an intramolecular autoproteolytic cleavage.". J. Biol. Chem. 267 (20): 14304–8. PMID 1629222. 
• Barr PJ, Mason OB, Landsberg KE, et al. (1991). "cDNA and gene structure for a human subtilisin-like protease with cleavage specificity for paired basic amino acid residues.". DNA Cell Biol. 10 (5): 319–28. doi:10.1089/dna.1991.10.319. PMID 1713771. 
• Herz J, Kowal RC, Goldstein JL, Brown MS (1990). "Proteolytic processing of the 600 kd low density lipoprotein receptor-related protein (LRP) occurs in a trans-Golgi compartment.". EMBO J. 9 (6): 1769–76. PMC 551881. PMID 2112085. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=551881. 
• van den Ouweland AM, van Duijnhoven HL, Keizer GD, et al. (1990). "Structural homology between the human fur gene product and the subtilisin-like protease encoded by yeast KEX2.". Nucleic Acids Res. 18 (3): 664. doi:10.1093/nar/18.3.664. PMC 333486. PMID 2408021. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=333486. 
• Van den Ouweland AM, Van Groningen JJ, Roebroek AJ, et al. (1989). "Nucleotide sequence analysis of the human fur gene.". Nucleic Acids Res. 17 (17): 7101–2. doi:10.1093/nar/17.17.7101. PMC 318436. PMID 2674906. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=318436. 
• Roebroek AJ, Schalken JA, Leunissen JA, et al. (1986). "Evolutionary conserved close linkage of the c-fes/fps proto-oncogene and genetic sequences encoding a receptor-like protein.". EMBO J. 5 (9): 2197–202. PMC 1167100. PMID 3023061. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1167100. 
• Molloy SS, Thomas L, VanSlyke JK, et al. (1994). "Intracellular trafficking and activation of the furin proprotein convertase: localization to the TGN and recycling from the cell surface.". EMBO J. 13 (1): 18–33. PMC 394775. PMID 7508380. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=394775. 
• Brakch N, Dettin M, Scarinci C, et al. (1995). "Structural investigation and kinetic characterization of potential cleavage sites of HIV GP160 by human furin and PC1.". Biochem. Biophys. Res. Commun. 213 (1): 356–61. doi:10.1006/bbrc.1995.2137. PMID 7639757. 
• Takahashi S, Kasai K, Hatsuzawa K, et al. (1993). "A mutation of furin causes the lack of precursor-processing activity in human colon carcinoma LoVo cells.". Biochem. Biophys. Res. Commun. 195 (2): 1019–26. doi:10.1006/bbrc.1993.2146. PMID 7690548. 
• Hendy GN, Bennett HP, Gibbs BF, et al. (1995). "Proparathyroid hormone is preferentially cleaved to parathyroid hormone by the prohormone convertase furin. A mass spectrometric study.". J. Biol. Chem. 270 (16): 9517–25. doi:10.1074/jbc.270.16.9517. PMID 7721880. 
• Dubois CM, Laprise MH, Blanchette F, et al. (1995). "Processing of transforming growth factor beta 1 precursor by human furin convertase.". J. Biol. Chem. 270 (18): 10618–24. doi:10.1074/jbc.270.18.10618. PMID 7737999. 
• Gu M, Rappaport J, Leppla SH (1995). "Furin is important but not essential for the proteolytic maturation of gp160 of HIV-1.". FEBS Lett. 365 (1): 95–7. doi:10.1016/0014-5793(95)00447-H. PMID 7774724. 
• Schäfer W, Stroh A, Berghöfer S, et al. (1995). "Two independent targeting signals in the cytoplasmic domain determine trans-Golgi network localization and endosomal trafficking of the proprotein convertase furin.". EMBO J. 14 (11): 2424–35. PMC 398356. PMID 7781597. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=398356. 
• Mbikay M, Seidah NG, Chrétien M, Simpson EM (1995). "Chromosomal assignment of the genes for proprotein convertases PC4, PC5, and PACE 4 in mouse and human.". Genomics 26 (1): 123–9. doi:10.1016/0888-7543(95)80090-9. PMID 7782070.