Control of peptide hormone biosynthesis by PC2 and 7B2

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DESCRIPTION (provided by applicant): The maturation of peptide hormones within secretory tissues such as the pancreas, pituitary and adrenal requires the participation of specific proteolytic converting enzymes, the prohormone convertases, and small convertase binding proteins such as 7B2 and proSAAS. However, the universal expression of these proteins in all endocrine and neural tissues (including tissues which lack cognate convertases) indicates that these small neuroendocrine proteins may have roles unrelated to their actions on convertases. In previous cycles of this grant we have mapped the interaction sites of 7B2 with proPC2 and have detailed how 7B2 acts to prevent unfolding and aggregation of proPC2. We have used 7B2 knockout animals first to describe an unexpected Cushing's disease-like pathology, and most recently to identify a surprising new role for this protein in weight homeostasis. This role was recently independently substantiated by the Medrano laboratory finding that the 7B2 gene represents a quantum trait locus for leanness. In the current proposal we will investigate the structure of 7B2 both alone and in association with proPC2. We will explore interesting new preliminary data that 7B2 may act to block the aggregation and oligomerization of other secretory proteins, such as synuclein and amyloid-generating peptides. Together with Dr. Juan Medrano, we will investigate 7B2- overexpressing mouse models in order to define how 7B2 expression can affect polygenic traits such as obesity. We will compare the profile of hypothalamic peptides generated in a subcongenic line of mice which overexpresses 7B2 (B62D3), will investigate direct effects of 7B2 administration on blood glucose and body weight, and will generate a specific 7B2-overexpressing transgenic mouse which we expect will exhibit a lean phenotype. This work has important implications for diseases involving peptide hormone synthesis, such as diabetes, and is also relevant to the study of obesity. Lastly, our chaperone studies may be pertinent to neurodegenerative diseases involving protein aggregation, such as Alzheimer's and Parkinson's disease. PUBLIC HEALTH RELEVANCE: The synthesis of peptide hormones such as insulin and glucagon depends on the interaction of peptide-synthesizing convertases with small binding proteins within neuroendocrine tissues. Recent work has shown that these small binding proteins, 7B2 and proSAAS, may have other important physiological roles, such as chaperone activity and involvement in body weight homeostasis. In the present proposal, we plan to investigate these other roles.