PCSK

PCSK refers to the proprotein convertase subtilisin/kexin-type family, a group of calcium-dependent serine proteases that activate a wide range of secreted and membrane proteins through proteolytic processing. These enzymes convert inactive proproteins into their active forms, enabling proper hormone production, growth factor signaling, receptor maturation, and, in some contexts, activation of viral proteins. PCSK enzymes function within the secretory pathway and are essential for numerous physiological processes across tissues.

Members of the PCSK family include PCSK1 (PC1/3), PCSK2 (PC2), PCSK3 (furin), PCSK4, PCSK5 (PC5/6), PCSK6 (PACE4), PCSK7 (PC7), and PCSK9. They differ in tissue distribution, substrate specificities, and subcellular localization. PCSK9 is notable for its extracellular action on the LDL receptor and its central role in cholesterol metabolism.

Biochemical mechanism: PCSKs are synthesized as inactive zymogens with an N-terminal prodomain; autoproteolysis removes the prodomain to yield an active enzyme. Activation requires calcium and a catalytic triad of aspartate, histidine, and serine in the catalytic domain. Localization in the trans-Golgi network, endosomes, or at the cell surface enables processing of proproteins such as proinsulin and other hormone precursors, prohormones like POMC, various growth factors, receptors, and viral envelope proteins. Substrates often feature multi-basic cleavage motifs.

Clinical relevance: Mutations in PCSK1 and PCSK2 disrupt endocrine peptide processing, contributing to obesity and other hormonal disorders. PCSK9 is a major regulator of cholesterol homeostasis; gain-of-function mutations raise LDL cholesterol, while PCSK9 inhibitors lower LDL levels and are used clinically to treat hypercholesterolemia. PCSK enzymes are widely studied as drug targets and as essential players in development, metabolism, and cellular signaling.