What lies ahead for the proprotein convertases?

Abstract

Limited proteolysis of secretory proteins is performed by one or more of the nine-membered proprotein convertase (PC) family: PC1/3, PC2, furin, PC4, PC5/6, PACE4, PC7, SKI-1/S1P, and PCSK9. The first seven proteinases cleave proproteins at single or pairs of basic residues in the Golgi, secretory granules, cell surface, or endosomes. These comprise neural and endocrine hormones and their release/inhibiting factors, growth factors and their receptors, and adhesion molecules. The regulated neural and endocrine PC1/3 and PC2 generate multiple peptide hormones and neuropeptides, including the family of hypothalamic-releasing/inhibiting factors. The ubiquitously expressed furin is the principal PC that processes constitutively secreted proteins. PC4 controls testicular and ovarian physiology. PC5/6 and PACE4 bind heparin sulfate proteoglycans and play critical roles during development by regulating body axis and polarity determinants. PC7 exerts unique functions in the brain. The members SKI-1/S1P and PCSK9 do not require a basic residue at the cleavage site and play major roles in the regulation of cholesterol/lipid homeostasis. In vivo studies demonstrated that PCs play major roles in health and disease states.