Furin

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Furin is an enzyme encoded by the FURIN gene in humans. Certain proteins are inactive when they are first synthesized, and certain parts must be removed to make them active. Furin cleaves these parts and activates the protein. It was named furin because it is located in the upstream region of the oncogene FES. The gene is called FUR (upstream region of FES), so the protein is named furin. Furin is also called PACE (paired alkaline amino acid lyase). Furin is a member of the S8 family and is a subtilisin-like peptidase.

Figure 1. Protein structure of furin.

Introductions

The protein encoded by this gene is an enzyme that belongs to the subtilisin-like proprotein convertase family. Members of this family are proprotein convertases, which process potential precursor proteins into their biologically active products. The encoded protein is a calcium-dependent serine endoprotease, which can effectively cleave the precursor protein at its paired basic amino acid processing site. Some of its substrates are: parathyroid hormone, transforming growth factor β1 precursor, protein albumin, pre β secretase, membrane type 1 matrix metalloproteinase, β subunit of pre nerve growth factor and von Willebrand factor. Furin-like proprotein convertase has been involved in the processing of RGMc (also known as Bloodjuvelin), a gene involved in severe iron overload disease (called juvenile hemochromatosis). Both Ganz and Rotwein groups demonstrated that furin-like proprotein convertase (PPC) is responsible for converting 50 kDa HJV into 40 kDa protein with a truncated COOH end at the conserved multiple RNRR site. This suggests a potential mechanism for the production of soluble forms of HJV/hemojuvelin (s-hemojuvelin) in the blood of rodents and humans. Furin is one of the proteases responsible for hydrolyzing the HIV envelope polyprotein precursor gp160 into gp120 and gp41 before virus assembly. This gene is thought to play a role in tumor progression. It has been found that alternative polyadenylation sites are used for this gene.

Structure

Furin is a proprotein convertase (PC) located in the trans-Golgi network (TGN) and is activated by an acidic pH environment. Furin can cleave precursor proteins with specific motifs to produce mature proteins with biological activity. If the P2 position is alkaline lysine or arginine, the cleavage efficiency can be increased by about 10 times. The researchers proved that the spike protein S1/S2 and S2' cleavage sites of the Bordet strain of infectious bronchitis virus (IBVs) can be recognized by pectin, which is a distinctive feature of IBV-Beaudette and other IBVs, and has Strong infection ability. According to the characteristics of furin's recognition substrate sequence, some short peptide inhibitors have been developed. However, the non-specific and irreversible inhibitory effects on all members of the PC series limit their applications. So far, no small molecule inhibitor of furin with good effect and high specificity has been found.

Functions

Furin is enriched in the Golgi apparatus and can cleave other proteins into mature/active forms. Furin cleaves proteins downstream of the basic amino acid target sequence (usually Arg-X-(Arg / Lys)-Arg'). In addition to processing cell precursor proteins, many pathogens also use furin. For example, viruses, HIV, influenza, dengue fever, several linear viruses such as Ebola virus and Marburg virus, and the envelope protein of the synaptic protein of SARS-CoV-2 must be cleaved by furin or furin. To become fully functional anthrax toxin like protease, Pseudomonas exotoxin and papilloma virus must undergo furin treatment when they first enter the host cell. Furin inhibitors are being considered as therapeutic agents for the treatment of anthrax infections. Furin is regulated by cholesterol and substrate presentation. When cholesterol is high, furin will be transported to the GM1 lipid raft. When cholesterol levels are low, furin will flow to the disordered area. It is speculated that this contributes to the initiation of cholesterol and age-dependent SARS-CoV.

Figure 2. Schematic of furin.