Metabolite Regulation of the Insulin Receptor Family

描述（改编自申请人摘要）：受体酪氨酸激酶 启动沿着对所有人都重要不同途径的信号传导 生活的方方面面。胰岛素受体家族具有保守的结构特征 这使得它在受体酪氨酸激酶中是独一无二的， 在生理条件下对腺嘌呤核苷酸代谢物库敏感 条件胰岛素受体（IR），胰岛素样生长因子-1受体 (IGF 1 R）和胰岛素受体相关受体（IRR）是异源四聚体 跨膜蛋白，与所有其他受体酪氨酸激酶相反 它们是单体的。胰岛素受体的非磷酸化状态是 以其激活回路的独特特征为标志： 抑制ATP和肽结合位点。胸骨内缓解 激活环自磷酸化的抑制需要一个构象 腺嘌呤核苷酸结合引起的变化。为了调和这些独特的 IR家族的特征，以及对蛋白激酶的更广泛理解 规则，我们将1。确定特定保守的 胰岛素受体家族中的残基对内质网抑制的作用。2.确定 是否对ATP的内质网抑制和构象敏感性 在人IGF 1 R和IRR中保守。3.确定构象 通过X射线晶体学分析的基础状态自磷酸化。这些研究将 阐明了新的性质的内部抑制和新的监管特点 控制受体自身磷酸化所必需的。的长期目标 这个项目将确定这些独特的功能可能服务 在环境和代谢应激条件下的发育中， 它们与慢性退行性疾病和胰岛素抵抗的可能联系 糖尿病和肥胖症。

DESCRIPTION(adapted from applicant's abstract): Receptor tyrosine kinases initiate signal transduction along diverse pathways that are important for all aspects of life. The insulin receptor family has conserved structural features that make it unique among receptor tyrosines kinases, and should render it sensitive to the adenine nucleotide metabolite pool under physiological conditions. The insulin receptor (IR), insulin-like growth factor-1 receptor (IGF 1 R) and insulin receptor-related receptor (IRR) are heterotetrameric transmembrane proteins, in contrast to all other receptor tyrosine kinases which are monomeric. The unphosphorylated state of the insulin receptor is marked by a unique feature of its activation loop: there is intrasteric inhibition of the ATP and peptide binding sites. Relief of intrasteric inhibition by activation Loop autophosphorylation requires a conformational change induced by adenine nucleotide binding. To reconcile these unique features of the IR family with the broader understanding of protein kinase regulation, we will 1. Determine the contributions of specific conserved residues to intrasteric inhibition in the insulin receptor family. 2. Determine whether intrasteric inhibition and conformational sensitivity to ATP are conserved in human IGF 1 R and IRR. 3. Determine the conformation for basal-state autophosphorylation by X-ray crystallography. These studies will elucidate new properties of intrasteric inhibition and new regulatory features necessary for controlled receptor autophosphorylation. The long-term goals of this project will be to determine the functions these unique features may serve in development under conditions of environmental and metabolic stress, and their possible links to chronic degenerative conditions and insulin resistance in diabetes and obesity.