Control of peptide hormone biosynthesis by PC2 and 7B2

描述（由申请人提供）：胰腺、垂体和肾上腺等分泌组织内肽激素的成熟需要特定的蛋白水解转化酶、激素原转化酶和小转化酶结合蛋白（如7B2和proSAAS）的参与。然而，这些蛋白在所有内分泌和神经组织（包括缺乏同源转化酶的组织）中的普遍表达表明，这些小的神经内分泌蛋白可能具有与其对转化酶的作用无关的作用。在之前的资助周期中，我们绘制了7B2与proPC2的相互作用位点，并详细介绍了7B2如何阻止proPC2的展开和聚集。我们首先使用7B2基因敲除动物来描述一种意想不到的库欣病样病理，最近发现了该蛋白在体重平衡中的令人惊讶的新作用。最近，Medrano实验室独立证实了这一作用，发现7B2基因代表了瘦的量子性状位点。在目前的提案中，我们将研究7B2单独和与proPC2联合的结构。我们将探索有趣的新的初步数据，即7B2可能阻断其他分泌蛋白的聚集和寡聚化，如突触核蛋白和淀粉样蛋白生成肽。与Juan Medrano博士一起，我们将研究7B2过表达的小鼠模型，以确定7B2表达如何影响肥胖等多基因特征。我们将比较过表达7B2 （B62D3）的小鼠亚基因系产生的下丘脑肽谱，将研究7B2给药对血糖和体重的直接影响，并将产生特异性的过表达7B2的转基因小鼠，我们预计该小鼠将表现出苗条的表型。这项工作对涉及肽激素合成的疾病（如糖尿病）具有重要意义，也与肥胖的研究有关。最后，我们的伴侣研究可能与涉及蛋白质聚集的神经退行性疾病有关，如阿尔茨海默病和帕金森病。公共卫生相关性：胰岛素和胰高血糖素等肽激素的合成依赖于神经内分泌组织内肽合成转换酶与小结合蛋白的相互作用。最近的研究表明，这些小的结合蛋白7B2和proSAAS可能具有其他重要的生理作用，如伴侣活性和参与体重稳态。在本提案中，我们计划研究这些其他作用。

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.