Proteolytic Processing Mechanisms in the Biosynthesis of Neuroendocrine Peptides: The Subtilisin-like Proprotein Convertases

Yves Rouillé, Stephen J. Duguay, Kaare Lund, Machi Furuta, Qiuming Gong, Gregory Lipkind, Anthony A. Oliva, Shu Jin Chan, Donald F. Steiner

Research output: Contribution to journalArticle

296 Citations (Scopus)

Abstract

The recent discovery of a novel family of precursor processing endoproteases has greatly accelerated progress in understanding the complex mechanisms underlying the maturation of prohormones, neuropeptides, and many other precursor-derived proteins. At least six members of this family have been found thus far in mammalian species, several having alternatively spliced isoforms, and related enzymes have been identified in many invertebrates, including molluscs, insects, nematodes, and coelenterates. The proprotein convertases are all dependent on calcium for activity and all possess highly conserved subtilisin-like domains with the characteristic catalytic triad of this serine protease (ordered Asp, His, and Ser along the polypeptide chain). Two members of this family, PC2(SPC2) 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 another important family member-furin/PACE (SPC1)-is expressed more ubiquitously, in almost all tissues, and at high levels in liver. SPC2 and SPC3 exhibit acidic pH optima and other properties which enhance their activity in the acidic, calcium-enriched environment of the dense-core 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 transmembrane domain. Furin processes a wide variety of precursors in the constitutive pathway, such as those of growth factors, receptors, coagulation factors, and viral glycoproteins. Recent findings on the processing of proopiomelanocortin, proinsulin, proglucagon, and several other neuroendocrine precursors by SPC2 and SPC3 are discussed, along with information on the structure, properties, evolution, developmental expression, and regulation or the convertases. An inherited defect in the fat/fat mouse which affects the processing of proinsulin, and probably also many other prohormones, due to a point mutation in carboxypeptidase E has recently been identified and has begun to provide new insights into the functional integration of the individual processing steps.

Original languageEnglish (US)
Pages (from-to)322-361
Number of pages40
JournalFrontiers in Neuroendocrinology
Volume16
Issue number4
DOIs
StatePublished - Oct 1995
Externally publishedYes

Fingerprint

Peptide Biosynthesis
Proprotein Convertases
Furin
Proinsulin
Carboxypeptidase H
Proglucagon
Fats
Calcium
trans-Golgi Network
Subtilisin
Neuroendocrine Cells
Pro-Opiomelanocortin
Neurosecretory Systems
Protein Precursors
Blood Coagulation Factors
Growth Factor Receptors
Mollusca
Secretory Vesicles
Serine Proteases
Invertebrates

Keywords

  • α-amidation
  • biosynthesis
  • carboxypeptidase E(H)
  • cDNA
  • hormones
  • peptides
  • subtilisin-like proprotein convertases

ASJC Scopus subject areas

  • Endocrine and Autonomic Systems
  • Endocrinology, Diabetes and Metabolism

Cite this

Proteolytic Processing Mechanisms in the Biosynthesis of Neuroendocrine Peptides : The Subtilisin-like Proprotein Convertases. / Rouillé, Yves; Duguay, Stephen J.; Lund, Kaare; Furuta, Machi; Gong, Qiuming; Lipkind, Gregory; Oliva, Anthony A.; Chan, Shu Jin; Steiner, Donald F.

In: Frontiers in Neuroendocrinology, Vol. 16, No. 4, 10.1995, p. 322-361.

Research output: Contribution to journalArticle

Rouillé, Yves ; Duguay, Stephen J. ; Lund, Kaare ; Furuta, Machi ; Gong, Qiuming ; Lipkind, Gregory ; Oliva, Anthony A. ; Chan, Shu Jin ; Steiner, Donald F. / Proteolytic Processing Mechanisms in the Biosynthesis of Neuroendocrine Peptides : The Subtilisin-like Proprotein Convertases. In: Frontiers in Neuroendocrinology. 1995 ; Vol. 16, No. 4. pp. 322-361.
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