PROTEOLYTIC PROCESSING MECHANISMS IN THE BIOSYNTHESIS OF NEUROENDOCRINE PEPTIDES - THE SUBTILISIN-LIKE PROPROTEIN CONVERTASES

The recent discovery of a novel family of precursor processing endopro teases has greatly accelerated progress in understanding the complex m echanisms underlying the maturation of prohormones, neuropeptides, and many other precursor-derived proteins. At least six members of this f amily have been found thus far in mammalian species, several having al ternatively spliced isoforms, and related enzymes have been identified in many invertebrates, including molluscs, insects, nematodes, and co elenterates. The proprotein convertases are all dependent on calcium f or activity and all possess highly conserved subtilisin-like domains w ith the characteristic catalytic triad of this serine protease (ordere d Asp, His, and Ser along the polypeptide chain). Two members of this family, PC2(SPCB) and PC1/PC3(SPC3), appear to play a preeminent role in neuroendocrine precursor processing. Both convertases are expressed only in the brain and in the extended neuroendocrine system, while an other important family member-furin/PACE (SPC1)-is expressed more ubiq uitously, in almost all tissues, and at high levels in liver. SPC2 and SPC3 exhibit acidic pH optima and other properties which enhance thei r activity in the acidic, calcium-enriched environment of the dense-co re secretory granules of the regulated pathway in neuroendocrine cells , while furin has a neutral pH optimum and is localized predominantly to the trans Golgi network where it is retained by a C-terminal transm embrane domain. Furin processes a wide variety of precursors in the co nstitutive pathway, such as those of growth factors, receptors, coagul ation factors, and viral glycoproteins. Recent findings on the process ing of proopiomelanocortin, proinsulin, proglucagon, and several other neuroendocrine precursors by SPC2 and SPC3 are discussed, along with information on the structure, properties, evolution, developmental exp ression, and regulation of the convertases. An inherited defect in the fat/fat mouse which affects the processing of proinsulin, and probabl y also many other prohormones, due to a point mutation in carboxypepti dase E has recently been identified and has begun to provide new insig hts into the functional integration of the individual processing steps . (C) 1995 Academic Press, Inc.