FURIN

FURIN is a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. It encodes a type 1 membrane bound protease that is expressed in many tissues, including neuroendocrine, liver, gut, and brain. The encoded protein undergoes an initial autocatalytic processing event in the ER and then sorts to the trans-Golgi network through endosomes where a second autocatalytic event takes place and the catalytic activity is acquired. The product of this gene is one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. Some of its substrates include 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. It is also thought to be one of the proteases responsible for the activation of HIV envelope glycoproteins gp160 and gp140 and may play a role in tumor progression. This gene is located in close proximity to family member proprotein convertase subtilisin/kexin type 6 and upstream of the FES oncogene.

Furin, Paired Basic Amino Acid Cleaving Enzyme

Ubiquitous endoprotease within constitutive secretory pathways capable of cleavage at the RX(K/R)R consensus motif (PubMed:11799113, PubMed:1629222, PubMed:1713771, PubMed:2251280, PubMed:24666235, PubMed:25974265, PubMed:7592877, PubMed:7690548, PubMed:9130696).

Mediates processing of TGFB1, an essential step in TGF-beta-1 activation (PubMed:7737999).

Converts through proteolytic cleavage the non-functional Brain natriuretic factor prohormone into its active hormone BNP(1-32) (PubMed:20489134, PubMed:21763278).

(Microbial infection) Cleaves and activates diphtheria toxin DT.

(Microbial infection) Cleaves and activates anthrax toxin protective antigen (PA).

(Microbial infection) Required for H7N1 and H5N1 influenza virus infection probably by cleaving hemagglutinin.

(Microbial infection) Able to cleave S.pneumoniae serine-rich repeat protein PsrP.

(Microbial infection) Facilitates human coronaviruses EMC and SARS-CoV-2 infections by proteolytically cleaving the spike protein at the monobasic S1/S2 cleavage site. This cleavage is essential for spike protein-mediated cell-cell fusion and entry into human lung cells.

(Microbial infection) Facilitates mumps virus infection by proteolytically cleaving the viral fusion protein F.

Amyloid fibril formation Source: Reactome
Blastocyst formation Source: Ensembl
Collagen catabolic process Source: Reactome
Dibasic protein processing Source: UniProtKB
Extracellular matrix disassembly Source: Reactome
Extracellular matrix organization Source: Reactome
Negative regulation of inflammatory response to antigenic stimulus Source: Reactome
Negative regulation of low-density lipoprotein particle receptor catabolic process Source: HGNC-UCL
Negative regulation of transforming growth factor beta1 production Source: BHF-UCL
Nerve growth factor production Source: BHF-UCL
Peptide biosynthetic process Source: BHF-UCL
Peptide hormone processing Source: BHF-UCL
Positive regulation of membrane protein ectodomain proteolysis Source: BHF-UCL
Positive regulation of transforming growth factor beta1 activation Source: UniProtKB
Protein processing Source: UniProtKB
Regulation of cholesterol transport Source: Ensembl
Regulation of endopeptidase activity Source: BHF-UCL
Regulation of lipoprotein lipase activity Source: Reactome
Regulation of protein catabolic process Source: BHF-UCL
Regulation of signal transduction Source: Ensembl
Secretion by cell Source: BHF-UCL
Signal peptide processing Source: HGNC-UCL
Transforming growth factor beta receptor signaling pathway Source: Reactome
Viral life cycle Source: BHF-UCL
Viral protein processing Source: Reactome
Zymogen activation Source: UniProtKB
Zymogen inhibition Source: UniProtKB

Trans-Golgi network membrane; Endosome membrane; Secreted; Cell membrane. Shuttles between the trans-Golgi network and the cell surface (PubMed:9412467, PubMed:11799113). Propeptide cleavage is a prerequisite for exit of furin molecules out of the endoplasmic reticulum (ER). A second cleavage within the propeptide occurs in the trans Golgi network (TGN), followed by the release of the propeptide and the activation of furin (PubMed:11799113).

Lumenal: 108-715
Helical: 716-738
Cytoplasmic: 739-794

The inhibition peptide, which plays the role of an intramolecular chaperone, is autocatalytically removed in the endoplasmic reticulum (ER) and remains non-covalently bound to furin as a potent autoinhibitor. Following transport to the trans Golgi, a second cleavage within the inhibition propeptide results in propeptide dissociation and furin activation.
Phosphorylation is required for TGN localization of the endoprotease. In vivo, exists as di-, mono- and non-phosphorylated forms.