Furin is a protease, a proteolytic enzyme activated by substrate presentation that in humans and other animals 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.[5][6][7][8] 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.[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 gp160 to 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]
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.[19]
Furin is regulated by cholesterol and substrate presentation. When cholesterol is high, furin traffics to GM1lipid 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.
^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. PMID1741956.
^"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.
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. PMID1713771.
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. PMID7639757.
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. PMID7690548.
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. S2CID21231590.
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. PMID7782070.
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.
