STRUCTURE OF INTERGRIN CYTOPLASMIC DOMAIN ALBB3

整合素细胞质结构域 ALBB3 的结构

• 批准号: 6013687
• 负责人: OLGA VINOGRADOVA
• 金额: $ 3.17万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6013687
• 关键词: biological signal transduction; circular dichroism; conformation; integrins; mutant; nuclear magnetic resonance spectroscopy; protein binding; protein structure function; structural biology

The inside-out signaling has been most clearly demonstrated for the platelet integrin alphaIIbbeta3: in unstimulated platelets, alphaIIbbeta3 exists in a "latent" noncompetent state - it does not bind its abundant blood-borne ligands such as fibrinogen, whereas upon stimulation with agonists, such as thrombin and ADP, alphaIIbbeta3 undergoes a conformational change and is subsequently activated to a high-affinity ligand binding state. This conformational change is thought to occur first in the cytoplasmic domain of alphaIIbbeta3, which then propagates through the transmembrane region to the extracellular domain resulting in high affinity ligand binding. The molecular details of the conformational transition for alphaIIbbeta3 cytoplasmic domain from its "closed inactive form" to the "open active state" remains poorly understood. It was recently shown that when inactive, the cytoplasmic tails of alphaIIbbeta3 interact with each other and with a divalent cation to form a ternary cytoplasmic domain complex. On the other hand, selective mutations on alphaIIb and/or beta3 tails result in constitutively active receptor, which suggests that the cytoplasmic domains of these active mutants adopt different conformation from the wild type. Thus the overall objective of this proposal is to gain insights into the conformation induced integrin signaling by determining structures of alphaIIbbeta3 cytoplasmic domain and its "active" mutants.

The inside-out signaling has been most clearly demonstrated for the platelet integrin alphaIIbbeta3: in unstimulated platelets, alphaIIbbeta3 exists in a "latent" noncompetent state - it does not bind its abundant blood-borne ligands such as fibrinogen, whereas upon stimulation with agonists, such as thrombin and ADP, alphaIIbbeta3 undergoes a conformational change and is随后激活至高亲和力的配体结合态。人们认为这种构象变化首先发生在Alphaiibbeta3的细胞质结构域中，然后通过跨膜区域传播到细胞外域，导致高亲和力配体结合。 Alphaiibbeta3细胞质结构域的构象转变的分子细节从其“封闭的无效形式”到“开放的活性状态”仍然鲜为人知。最近显示，当无活性时，alphaiibbeta3的细胞质尾巴相互相互作用，并与二价阳离子相互作用，形成三元细胞质结构域复合物。另一方面，α和/或β3尾部上的选择性突变导致组成性活性受体，这表明这些活性突变体的细胞质结构域采用与野生型不同的构象。因此，该提案的总体目标是通过确定Alphaiibbeta3细胞质结构域及其“活跃”突变体的结构来洞悉构象引起的整联蛋白信号传导。