Processing of cocaine- and amphetamine-regulated transcript (CART) precursor proteins by prohormone convertases (PCs) and its implications

Cocaine- and amphetamine-regulated transcript (CART) peptides are expressed in several neuroendocrine tissues, including hypothalamus, pituitary, gut, adrenal and pancreas, and are involved in regulating important biological processes including feeding/appetite, drug reward and stress. CART is synthesized as larger, inactive peptide precursors (pro-CART) that require endoproteolytic processing to generate smaller, active forms. Prohormone/proprotein convertases (PCs), a family of calcium-dependent, serine endoproteases, have been shown to cleave many protein precursors in the regulated/constitutive secretory pathway to generate smaller fragments. In our previous studies, we have demonstrated the important roles of the two neuroendocrine-specific PCs, PC2 and PC1/3, in processing the two pro-CART isoforms, long (102aa) and short (89aa), to generate the bioactive CART peptides, I (55-102/42-89) and II (62-102/49-89) as well as the intermediate fragments, 10-89 and 33-102. Our subsequent studies have revealed the participation of another PC family member, PC5/6A (the soluble isoform of a widely expressed PC, PC5/6), in cleaving both precursor isoforms. We conclude that PC5/6A contributes to the normal efficient processing of pro-CART and is functionally more redundant with PC2 than PC1/3 in generating both CART I and II.