Furin is a protein that in humans is encoded by the FURINgene. 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.[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).
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), 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 one of the proteases responsible for the proteolytic cleavage of HIV envelope polyprotein precursor gp160 to gp120 and gp41 prior to viral assembly.[7] 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.[8] 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, dengue fever and several filoviruses including ebola and marburg virus must be cleaved by furin or furin-like proteases to become fully functional. Anthrax toxin, pseudomonasexotoxin, 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.[9]
The furin substrates and the locations of furin cleavage sites in protein sequences can be predicted by two bioinformatics methods: ProP [10] and PiTou.[11]
Expression of furin in T-cells is required for maintenance of peripheral immune tolerance.[12]
↑Kiefer MC, Tucker JE, Joh R, Landsberg KE, Saltman D, Barr PJ (Dec 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. PMID1741956.
↑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 (Jul 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. PMID17537721.
↑Duckert P, Brunak S, Blom N (Jan 2004). "Prediction of proprotein convertase cleavage sites". Protein Engineering, Design & Selection. 17 (1): 107–112. doi:10.1093/protein/gzh013. PMID14985543.
↑Wan L, Molloy SS, Thomas L, Liu G, Xiang Y, Rybak SL, Thomas G (Jul 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. PMID9695949.
Hallenberger S, Bosch V, Angliker H, Shaw E, Klenk HD, Garten W (Nov 1992). "Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gp160". Nature. 360 (6402): 358–61. doi:10.1038/360358a0. PMID1360148.
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. PMID1571548.
Leduc R, Molloy SS, Thorne BA, Thomas G (Jul 1992). "Activation of human furin precursor processing endoprotease occurs by an intramolecular autoproteolytic cleavage". The Journal of Biological Chemistry. 267 (20): 14304–8. PMID1629222.
Barr PJ, Mason OB, Landsberg KE, Wong PA, Kiefer MC, Brake AJ (Jun 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. PMID1713771.
Brakch N, Dettin M, Scarinci C, Seidah NG, Di Bello C (Aug 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. PMID7639757.
Takahashi S, Kasai K, Hatsuzawa K, Kitamura N, Misumi Y, Ikehara Y, Murakami K, Nakayama K (Sep 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. PMID7690548.
Hendy GN, Bennett HP, Gibbs BF, Lazure C, Day R, Seidah NG (Apr 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. PMID7721880.
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. PMID7737999.
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. PMID7774724.
Mbikay M, Seidah NG, Chrétien M, Simpson EM (Mar 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. PMID7782070.
