Furin

Furin Domain Structure, Classification and Biological Role

Encoded by the FURIN gene, furin (also known as PACE or Paired basic Amino acid Cleaving Enzyme) is a Type I transmembrane protein and a member of the proprotein convertase family, which forms part of the subtilisin super family of serine endoproteases.

When expressed, the furin peptide contains a signal peptide, which enables the pro-enzyme to be trafficked into the endoplasmic reticulum (ER). Furin also contains prodomains that are flanked by a signal peptidase cleavage site on the amino-terminal side, and by basic amino acids that make up the autoproteolytic cleavage site on the carboxy-terminal side.

Before furin becomes an active enzyme, it must undergo an initial multistep autocatalytic processing event, which involves a compartment-specific pair of cleavages in the prodomain; this is essential to allow for its catalytic centre to fold properly. The first cleavage (t½ = 10 mins), takes place in the pH neutral ER, in the consensus furin cleavage site, adjacent to the catalytic domain (-Arg-Thr-Lys-Arg¹⁰⁷). The second cleavage (t½ < 2 hrs) occurs while the propeptide-furin complex is being trafficked within the mildly acidic trans-Golgi network/endosomal system. This cleavage occurs in the pH-sensitive propeptide cleavage site in the prodomain (-Arg70-Gly-Val-Thr-Lys-Arg⁷⁵). The resulting product is an active furin enzyme that is able to cleave its substrate at single or paired basic residues.

Furin plays a key role in embryogenesis, catalyzing hormones, growth factors receptors and extracellular matrix enzymes among others. Furin's activity has been implicated in neuronal innervation, cell fate and dynamic regulation of juxtacrine and paracrine signaling.

Role of Furin in Disease States

In addition to its essential role in multiple signaling pathways, furin has been leveraged by multiple pathogens to enter cells. Furin plays a key role in activating many pathogenic agents, including Ebola, anthrax and avian influenza. Furin has also been shown to activate the HIV envelope glycoproteins gp160 and gp140. Furthermore, dysregulation of furin expression has been linked to cancer, and dementia. High levels of furin in multiple cancer types is correlated with the increased aggressiveness, which may be linked to increased levels of membrane type 1-matrix metalloproteinase, one of furin's substrates

Furin and Cell Entry Mechanisms of SARS-CoV-2

Coronaviruses contain a trimeric transmembrane spike (S) glycoprotein, which is essential for viral cell entry. The S glycoprotein contains two functional domains: a receptor binding domain, and a domain that allows fusion of the viral and host cell membranes. The S glycoprotein must be cleaved by a cell protease to reveal the active fusion sequences. Unlike most coronaviruses, including SARS-CoV, the spike protein of SARS-CoV-2 (the virus responsibe for the COVID-19 pandemic) is thought to be cleaved by furin. In support of this hypothesis, a study had shown that pre-activation with furin enhances SARS-CoV-2 pseudovirus entry into BHK cells.

Figure 1: Structure of Furin. Structure taken from Protein Data Bank, PDBID: 1P8J. Henrich et al (2003) The Crystal Structure of the Proprotein Processing Proteinase Furin Explains its Stringent Specificity. Nat Struct Biol 10: 520-526

External sources of pharmacological information for Furin :

• IUPHAR Receptor Code