7B2 is an acidic protein residing in the secretory granules of neuroendocrine cells. Its sequence has been elucidated in many phyla and species. It shows high similarity among mammals. A Pro-Pro-Asn-Pro-Cys-Pro polyproline motif is its most conserved feature, being carried by both vertebrate and invertebrate sequences. It is biosynthesized as a precursor protein that is cleaved into an N-terminal fragment and a C-terminal peptide. In neuroendocrine cells, 7B2 functions as a specific chaperone for the proprotein convertase (PC) 2. Through the sequence around its Pro-Pro-Asn-Pro-Cys-Pro motif, it binds to an inactive proPC2 and facilitates its transport from the endoplasmic reticulum to later compartments of the secretory pathway where the zymogen is proteolytically matured and activated. Its C-terminal peptide can inhibit PC2 in vitro and may contribute to keep the enzyme transiently inactive in vivo. The PC2–7B2 model defines a new neuroendocrine paradigm whereby proteolytic activation of prohormones and proneuropeptides in the secretory pathway is spatially and temporally regulated by the dynamics of interactions between converting enzymes and their binding proteins. Interestingly, unlike PC2-null mice, which are viable, 7B2-null mutants die early in life from Cushing's disease due to corticotropin (‘ACTH’) hypersecretion by the neurointermediate lobe, suggesting a possible involvement of 7B2 in secretory granule formation and in secretion regulation. The mechanism of this regulation is yet to be elucidated. 7B2has been shown to be a good marker of several neuroendocrine cell dysfunctions in humans. The possibility that anomalies in its structure and expression could be aetiological causes of some of these dysfunctions warrants investigation.
- proprotein convertase
- proteolytic processing
Abbreviations used: AP, activator protein; 7B2CT, C-terminal domain of 7B2; CPE, carboxypeptidase E; CRE, cAMP-responsive element; CRF, corticotropin-releasing factor; DTT, dithiothreitol; ER, endoplasmic reticulum; GH, growth hormone; IBMX, 3-isobutyl-1-methyl-xanthine; IGF, insulin-like growth factor; LHRH, luteinizing hormone-releasing hormone; β-LPH, β-lipotropic hormone; PACE, paired basic amino acid converting enzyme; PC, proprotein convertase; POMC, pro-opiomelanocortin; PWS, Prader–Willi syndrome; SH3, Src homology 3; TGN, trans-Golgi network; UTR, untranslated region; VP, vasopressin.
- The Biochemical Society, London ©2001