Furin
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| Location (UCSC) | Chr 15: 90.87 – 90.88 Mb | Chr 7: 80.04 – 80.06 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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Furin is a
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
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.[9][10]
The furin substrates and the locations of furin cleavage sites in protein sequences can be predicted by two bioinformatics methods: ProP[11] and PiTou.[12]
Clinical significance
Furin is one of the proteases responsible for the proteolytic cleavage of HIV envelope polyprotein precursor
gp120 and gp41 prior to viral assembly.[13] This protease is also thought to play a role in tumor progression.[7] The use of alternate polyadenylation sites has been found for the FURIN gene.[citation needed
]
Furin is enriched in the Golgi apparatus, where it functions to cleave other proteins into their mature/active forms.[14] 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,[15][16][17] 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.[18]
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.[19]
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.[20] 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.[21]
Interactions
Furin has been shown to
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000140564 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030530 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 2251280.
- PMID 1741956.
- ^ a b "Entrez Gene: FURIN furin (paired basic amino acid cleaving enzyme)".
- PMID 3023061.
- PMID 17869549.
- PMID 18384687.
- PMID 14985543.
- PMID 22355773.
- S2CID 4306605.
- PMID 12360192.
- PMID 32057769.
- PMID 32362314.
- ^ "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.
- PMID 34611326.
- PMID 17537721.
- PMID 32511366.
- PMID 18701887.
- 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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.
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