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FURIN
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4OMC, 4OMD, 4RYD, 4Z2A
Identifiers
Aliases	FURIN, FUR, PACE, PCSK3, SPC1, furin, paired basic amino acid cleaving enzyme
External IDs	OMIM: 136950; MGI: 97513; HomoloGene: 1930; GeneCards: FURIN; OMA:FURIN - orthologs
Gene location (Human) Chr. Chromosome 15 (human) Band 15q26.1 Start 90,868,588 bp End 90,883,458 bp
Gene location (Mouse) Chr. Chromosome 7 (mouse) Band 7 D2|7 45.65 cM Start 80,038,333 bp End 80,055,184 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lobe of liver body of pancreas right lung right lobe of thyroid gland left lobe of thyroid gland apex of heart skin of leg upper lobe of left lung salivary gland anterior pituitary Top expressed in epithelium of stomach Ileal epithelium parotid gland granulocyte lip right kidney lactiferous gland corneal stroma extensor digitorum longus muscle secondary oocyte More reference expression data BioGPS More reference expression data
Gene ontology Molecular function nerve growth factor binding peptide binding metal ion binding protease binding peptidase activity protein binding serine-type endopeptidase inhibitor activity serine-type peptidase activity hydrolase activity endopeptidase activity serine-type endopeptidase activity Cellular component integral component of membrane Golgi apparatus membrane plasma membrane cell surface trans-Golgi network endoplasmic reticulum Golgi lumen membrane raft trans-Golgi network transport vesicle extracellular exosome extracellular space Golgi membrane extracellular region endosome endosome membrane integral component of Golgi membrane Biological process negative regulation of low-density lipoprotein particle receptor catabolic process negative regulation of transforming growth factor beta1 production viral life cycle secretion by cell peptide biosynthetic process protein processing positive regulation of membrane protein ectodomain proteolysis extracellular matrix disassembly extracellular matrix organization viral protein processing proteolysis signal peptide processing peptide hormone processing regulation of signal transduction regulation of protein catabolic process collagen catabolic process negative regulation of nerve growth factor production nerve growth factor processing nerve growth factor production cell population proliferation transforming growth factor beta receptor signaling pathway regulation of endopeptidase activity negative regulation of endopeptidase activity cornification zymogen activation regulation of lipoprotein lipase activity dibasic protein processing zymogen inhibition positive regulation of transforming growth factor beta1 activation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5045 18550 Ensembl ENSG00000140564 ENSMUSG00000030530 UniProt P09958 P23188 RefSeq (mRNA) NM_002569 NM_001289823 NM_001289824 NM_001081454 NM_011046 RefSeq (protein) NP_001276752 NP_001276753 NP_002560 NP_001369548 NP_001369549 NP_001369550 NP_001369551 NP_001276752.1 NP_001276753.1 NP_002560.1 NP_001074923 NP_035176 Location (UCSC) Chr 15: 90.87 – 90.88 Mb Chr 7: 80.04 – 80.06 Mb PubMed search
Wikidata
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Furin is a protease, a proteolytic enzyme activated by substrate presentation that in humans and other animals is encoded by the FURIN gene. Some proteins are inactive when they are first synthesized, and must have sections removed in order to become active. Furin cleaves these sections and activates the proteins. 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). A member of family S8, furin is a subtilisin-like peptidase.

Function

The protein encoded by this gene is an enzyme that 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), 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.

The furin substrates and the locations of furin cleavage sites in protein sequences can be predicted by two bioinformatics methods: ProP and PiTou.

Clinical significance

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

Furin is enriched in the Golgi apparatus, where it functions to cleave other proteins into their mature/active forms. 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 used by a number of pathogens. For example, the envelope proteins of viruses such as HIV, influenza, dengue fever, several filoviruses including ebola and marburg virus, and the spike protein of SARS-CoV-2, must be cleaved by furin or furin-like proteases to become fully functional. When SARS-CoV-2 virus is being synthesized in an infected cell, furin or furin-like proteases cleave the spike protein into two portions (S1 and S2), which remain associated.

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.

Furin is regulated by cholesterol and substrate presentation. When cholesterol is high, furin traffics to GM1 lipid rafts. When cholesterol is low, furin traffics to the disordered region. This is speculated to contribute to cholesterol and age dependent priming of SARS-CoV.

Expression of furin in T-cells is required for maintenance of peripheral immune tolerance.

Interactions

Furin has been shown to interact with PACS1.

References

1. ^ GRCh38: Ensembl release 89: ENSG00000140564 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000030530 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Wise RJ, Barr PJ, Wong PA, Kiefer MC, Brake AJ, Kaufman RJ (December 1990). "Expression of a human proprotein processing enzyme: correct cleavage of the von Willebrand factor precursor at a paired basic amino acid site". Proceedings of the National Academy of Sciences of the United States of America. 87 (23): 9378–82. Bibcode:1990PNAS...87.9378W. doi:10.1073/pnas.87.23.9378. PMC 55168. PMID 2251280.
6. Kiefer MC, Tucker JE, Joh R, Landsberg KE, Saltman D, Barr PJ (December 1991). "Identification of a second human subtilisin-like protease gene in the fes/fps region of chromosome 15". DNA and Cell Biology. 10 (10): 757–69. doi:10.1089/dna.1991.10.757. PMID 1741956.
7. ^ "Entrez Gene: FURIN furin (paired basic amino acid cleaving enzyme)".
8. 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". The EMBO Journal. 5 (9): 2197–202. doi:10.1002/j.1460-2075.1986.tb04484.x. PMC 1167100. PMID 3023061.
9. 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, Molecules & Diseases. 40 (1): 122–31. doi:10.1016/j.bcmd.2007.06.023. PMC 2211380. PMID 17869549.
10. Kuninger D, Kuns-Hashimoto R, Nili M, Rotwein P (April 2008). "Pro-protein convertases control the maturation and processing of the iron-regulatory protein, RGMc/hemojuvelin". BMC Biochemistry. 9: 9. doi:10.1186/1471-2091-9-9. PMC 2323002. PMID 18384687.
11. Duckert P, Brunak S, Blom N (January 2004). "Prediction of proprotein convertase cleavage sites". Protein Engineering, Design & Selection. 17 (1): 107–12. doi:10.1093/protein/gzh013. PMID 14985543.
12. Tian S, Huajun W, Wu J (February 2012). "Computational prediction of furin cleavage sites by a hybrid method and understanding mechanism underlying diseases". Scientific Reports. 2: 261. Bibcode:2012NatSR...2E.261T. doi:10.1038/srep00261. PMC 3281273. PMID 22355773.
13. Hallenberger S, Bosch V, Angliker H, Shaw E, Klenk HD, Garten W (November 1992). "Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gp160". Nature. 360 (6402): 358–61. Bibcode:1992Natur.360..358H. doi:10.1038/360358a0. PMID 1360148. S2CID 4306605.
14. Thomas G (October 2002). "Furin at the cutting edge: from protein traffic to embryogenesis and disease". Nature Reviews. Molecular Cell Biology. 3 (10): 753–66. doi:10.1038/nrm934. PMC 1964754. PMID 12360192.
15. Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E (April 2020). "The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade". Antiviral Research. 176: 104742. doi:10.1016/j.antiviral.2020.104742. PMC 7114094. PMID 32057769.
16. Hoffmann M, Kleine-Weber H, Pöhlmann S (May 2020). "A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells". Molecular Cell. 78 (4): 779–784.e5. doi:10.1016/j.molcel.2020.04.022. PMC 7194065. PMID 32362314.
17. "The origin of COVID-19: Evidence piles up, but the jury's still out". 11 October 2021. The furin cleavage site on the SARS-CoV-2 virus allows its spikes to be cut and "primed" as it moves out of one cell and into another. The site is thought to make the virus more transmissible.
18. Jackson CB, Farzan M, Chen B, Choe H (2022). "Mechanisms of SARS-CoV-2 entry into cells". Nature Reviews Molecular Cell Biology. 23 (1): 3–20. doi:10.1038/s41580-021-00418-x. PMC 8491763. PMID 34611326.
19. Shiryaev SA, Remacle AG, Ratnikov BI, Nelson NA, Savinov AY, Wei G, et al. (July 2007). "Targeting host cell furin proprotein convertases as a therapeutic strategy against bacterial toxins and viral pathogens". The Journal of Biological Chemistry. 282 (29): 20847–53. doi:10.1074/jbc.M703847200. PMID 17537721.
20. Wang H, Yuan Z, Pavel MA, Jablonski SM, Jablonski J, Hobson R, et al. (June 2021). "The role of high cholesterol in age-related COVID19 lethality". bioRxiv: 2020.05.09.086249. doi:10.1101/2020.05.09.086249. PMC 7263494. PMID 32511366.
21. Pesu M, Watford WT, Wei L, Xu L, Fuss I, Strober W, et al. (September 2008). "T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance". Nature. 455 (7210): 246–50. Bibcode:2008Natur.455..246P. doi:10.1038/nature07210. PMC 2758057. PMID 18701887.
22. Wan L, Molloy SS, Thomas L, Liu G, Xiang Y, Rybak SL, Thomas G (July 1998). "PACS-1 defines a novel gene family of cytosolic sorting proteins required for trans-Golgi network localization". Cell. 94 (2): 205–16. doi:10.1016/S0092-8674(00)81420-8. PMID 9695949. S2CID 15027198.

Further reading

• Nakayama K (November 1997). "Furin: a mammalian subtilisin/Kex2p-like endoprotease involved in processing of a wide variety of precursor proteins". The Biochemical Journal. 327 ( Pt 3) (3): 625–35. doi:10.1042/bj3270625. PMC 1218878. PMID 9599222.
• Bassi DE, Mahloogi H, Klein-Szanto AJ (June 2000). "The proprotein convertases furin and PACE4 play a significant role in tumor progression". Molecular Carcinogenesis. 28 (2): 63–9. doi:10.1002/1098-2744(200006)28:2<63::AID-MC1>3.0.CO;2-C. PMID 10900462. S2CID 22849623.
• Hallenberger S, Bosch V, Angliker H, Shaw E, Klenk HD, Garten W (November 1992). "Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gp160". Nature. 360 (6402): 358–61. Bibcode:1992Natur.360..358H. doi:10.1038/360358a0. PMID 1360148. S2CID 4306605.
• Rehemtulla A, Kaufman RJ (May 1992). "Preferred sequence requirements for cleavage of pro-von Willebrand factor by propeptide-processing enzymes". Blood. 79 (9): 2349–55. doi:10.1182/blood.V79.9.2349.2349. PMID 1571548.
• Leduc R, Molloy SS, Thorne BA, Thomas G (July 1992). "Activation of human furin precursor processing endoprotease occurs by an intramolecular autoproteolytic cleavage". The Journal of Biological Chemistry. 267 (20): 14304–8. doi:10.1016/S0021-9258(19)49712-3. PMID 1629222.
• Barr PJ, Mason OB, Landsberg KE, Wong PA, Kiefer MC, Brake AJ (June 1991). "cDNA and gene structure for a human subtilisin-like protease with cleavage specificity for paired basic amino acid residues". DNA and Cell Biology. 10 (5): 319–28. doi:10.1089/dna.1991.10.319. PMID 1713771.
• Herz J, Kowal RC, Goldstein JL, Brown MS (June 1990). "Proteolytic processing of the 600 kd low density lipoprotein receptor-related protein (LRP) occurs in a trans-Golgi compartment". The EMBO Journal. 9 (6): 1769–76. doi:10.1002/j.1460-2075.1990.tb08301.x. PMC 551881. PMID 2112085.
• van den Ouweland AM, van Duijnhoven HL, Keizer GD, Dorssers LC, Van de Ven WJ (February 1990). "Structural homology between the human fur gene product and the subtilisin-like protease encoded by yeast KEX2". Nucleic Acids Research. 18 (3): 664. doi:10.1093/nar/18.3.664. PMC 333486. PMID 2408021.
• Van den Ouweland AM, Van Groningen JJ, Roebroek AJ, Onnekink C, Van de Ven WJ (September 1989). "Nucleotide sequence analysis of the human fur gene". Nucleic Acids Research. 17 (17): 7101–2. doi:10.1093/nar/17.17.7101. PMC 318436. PMID 2674906.
• 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". The EMBO Journal. 5 (9): 2197–202. doi:10.1002/j.1460-2075.1986.tb04484.x. PMC 1167100. PMID 3023061.
• Molloy SS, Thomas L, VanSlyke JK, Stenberg PE, Thomas G (January 1994). "Intracellular trafficking and activation of the furin proprotein convertase: localization to the TGN and recycling from the cell surface". The EMBO Journal. 13 (1): 18–33. doi:10.1002/j.1460-2075.1994.tb06231.x. PMC 394775. PMID 7508380.
• Brakch N, Dettin M, Scarinci C, Seidah NG, Di Bello C (August 1995). "Structural investigation and kinetic characterization of potential cleavage sites of HIV GP160 by human furin and PC1". Biochemical and Biophysical Research Communications. 213 (1): 356–61. doi:10.1006/bbrc.1995.2137. PMID 7639757.
• Takahashi S, Kasai K, Hatsuzawa K, Kitamura N, Misumi Y, Ikehara Y, et al. (September 1993). "A mutation of furin causes the lack of precursor-processing activity in human colon carcinoma LoVo cells". Biochemical and Biophysical Research Communications. 195 (2): 1019–26. doi:10.1006/bbrc.1993.2146. PMID 7690548.
• Hendy GN, Bennett HP, Gibbs BF, Lazure C, Day R, Seidah NG (April 1995). "Proparathyroid hormone is preferentially cleaved to parathyroid hormone by the prohormone convertase furin. A mass spectrometric study". The Journal of Biological Chemistry. 270 (16): 9517–25. doi:10.1074/jbc.270.16.9517. PMID 7721880.
• Dubois CM, Laprise MH, Blanchette F, Gentry LE, Leduc R (May 1995). "Processing of transforming growth factor beta 1 precursor by human furin convertase". The Journal of Biological Chemistry. 270 (18): 10618–24. doi:10.1074/jbc.270.18.10618. PMID 7737999.
• Gu M, Rappaport J, Leppla SH (May 1995). "Furin is important but not essential for the proteolytic maturation of gp160 of HIV-1". FEBS Letters. 365 (1): 95–7. doi:10.1016/0014-5793(95)00447-H. PMID 7774724. S2CID 21231590.
• Schäfer W, Stroh A, Berghöfer S, Seiler J, Vey M, Kruse ML, et al. (June 1995). "Two independent targeting signals in the cytoplasmic domain determine trans-Golgi network localization and endosomal trafficking of the proprotein convertase furin". The EMBO Journal. 14 (11): 2424–35. doi:10.1002/j.1460-2075.1995.tb07240.x. PMC 398356. PMID 7781597.
• Mbikay M, Seidah NG, Chrétien M, Simpson EM (March 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.

External links

• Overview of all the structural information available in the PDB for UniProt: P09958 (Human Furin) at the PDBe-KB.
• Overview of all the structural information available in the PDB for UniProt: P23188 (Mouse Furin) at the PDBe-KB.

• Biology

• Genes on human chromosome 15
• EC 3.4.21