Furin

Furin is a calcium-dependent serine protease that activates many proteins by cutting them after a cluster of basic amino acids as they pass through the secretory pathway. It is the best-studied member of the proprotein convertase family. Many hormones, growth factors, receptors, and enzymes are made as inactive precursors (proproteins) that become functional only after furin cleaves them.

Furin matters well beyond normal cell biology, because many viruses and bacterial toxins exploit it to activate themselves. One example is the furin cleavage site in the SARS-CoV-2 spike protein, which became one of the most discussed molecular features of the COVID-19 pandemic.

Furin is encoded by the FURIN gene on human chromosome 15. Its name comes from FES upstream region, because the gene was discovered next to the FES oncogene. Furin is related to bacterial subtilisin and has a catalytic triad of aspartate, histidine, and serine, like other serine proteases. It is a type I membrane protein with a catalytic domain, a "P domain" that stabilizes it, and a short tail in the cytoplasm that controls where it travels in the cell.

Furin itself is made as an inactive precursor that cuts itself to become active in the endoplasmic reticulum. It then works mainly in the trans-Golgi network of the Golgi apparatus, where it meets proteins on their way out of the cell. It cycles between the Golgi, the cell surface, and endosomes, and active furin can also be shed into the extracellular space.

Furin recognizes a short stretch of amino acids rich in arginine (R) and lysine (K). Its preferred motif is

R–X–(K/R)–R↓

where X is any amino acid and the arrow marks the cut. The minimal requirement is R–X–X–R, with an arginine in the position just before the cut. Because the motif includes several positively charged (basic) residues, such sites are often called polybasic cleavage sites. Cleavage breaks a peptide bond and typically releases a prodomain or splits a precursor into two chains that stay associated.

Furin is active in nearly all tissues and processes a wide range of substrates, including:

• Growth factors and their regulators, such as pro-TGF-β and pro-nerve growth factor.
• Receptors, such as the insulin receptor precursor, which furin splits into its α and β chains.
• Enzymes that remodel tissue, such as the membrane-type matrix metalloproteinases.
• Blood proteins, such as von Willebrand factor, which is needed for clotting.

Mice lacking furin die during embryonic development, which shows the enzyme is essential. Related convertases (such as PC1/3 and PC2, which process proinsulin in pancreatic cells) handle more specialized substrates.

Because furin sits on the main exit route of the cell and is present almost everywhere, many pathogens have evolved cleavage sites that it recognizes:

• Bacterial toxins: Anthrax protective antigen, diphtheria toxin, and Pseudomonas exotoxin A must be cut by furin before they can deliver their toxic parts into cells.
• Avian influenza: Highly pathogenic H5 and H7 bird flu viruses carry a polybasic cleavage site in their hemagglutinin. Because furin is present in many tissues, these viruses can spread through the whole body, whereas low-pathogenic strains depend on proteases found mainly in the respiratory and gut linings.
• HIV: The envelope precursor gp160 is cut by furin into gp120 and gp41, which is needed for the virus to infect cells.
• SARS-CoV-2: The coronavirus behind COVID-19 has a furin site (PRRAR) at the S1/S2 boundary of its spike protein, which SARS-CoV and its closest relatives lack. Cutting at this site during virus production primes the spike for later activation by the host protease TMPRSS2. This enhances infection of airway cells and spread between hosts in experimental studies.

Furin is being studied as a drug target for infections and some cancers, in which high furin activity can promote tumor growth and invasion. Because furin is essential for normal physiology, broad inhibition carries a risk of side effects. Research has therefore focused on targeted or short-term inhibition, and on understanding how pathogens adapt their cleavage sites, a recurring theme in virus evolution and proteins biochemistry.