Metabolite Regulation of the Insulin Receptor Family

描述(摘自申请者摘要)：受体酪氨酸激酶 沿着对所有人都很重要的不同途径启动信号转导 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，应该会使它 生理状态下对腺嘌呤核苷酸代谢物库的敏感性 条件。胰岛素受体(IR)、胰岛素样生长因子-1受体 胰岛素样生长因子1受体(IGF1 R)和胰岛素受体相关受体(IRR)是异四聚体 跨膜蛋白，与所有其他受体酪氨酸激酶不同 它们都是单体。胰岛素受体的非磷酸化状态是 以其激活环的一个独特特征为特点：存在空间内 抑制三磷酸腺苷和多肽结合部位。缓解体内的立体效应 激活环自动磷酸化抑制需要构象 腺嘌呤核苷酸结合引起的改变。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 调控，我们将1.确定具体保守的贡献 胰岛素受体家族中的残留到空间内抑制。2.确定 对ATP的空间构象抑制和构象敏感性是否 在人IGF1R和IRR中保守。3.确定其构象 X-射线结晶学的基态自动磷酸化。这些研究将 阐明空间内抑制的新特性和新的调控特征 是受控受体自动磷酸化所必需的。的长期目标 该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发育，以及 它们可能与慢性退行性疾病和胰岛素抵抗有关 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.