Role of Calcium Binding in Alpha IIb Integrin Biogenesis

描述（由申请人提供）： 血小板整合素α-IIb-β 3介导血小板聚集， 止血的关键作用。无功能性α IIb-β 3的患者 受体在出血性疾病Glanzmann血小板无力症（GT）中表现。 通过以下能力，突出了β 1 Ib-β 3的医学重要性： β 3受体拮抗剂预防不稳定性心肌缺血并发症 心绞痛和经皮冠状动脉介入治疗。中的一些突变 提交人b表示，GT中的结果已显示完全阻塞 成熟加工的蛋白质，导致蛋白质保留在 内质网（ER）。特别是，四个基因中及其周围的突变 α 1 Ib的阳离子结合域普遍导致ER滞留。这些 GT的特定病例包括由以下引起的遗传性疾病的范例： 蛋白质结构的构象变化，导致异常ER 加工，并最终导致ER保留和降解。的 α 1 Ib阳离子结合域具有高度保守的疏水残基 受体复合物正常生物合成所需的蛋白质。甚至 这些区域中的保守氨基酸取代深刻地影响了 α 1 Ib表达水平和成熟程度。这些数据表明 阳离子结合域的保守变化改变了它们的 结构，这会影响其阳离子结合亲和力。这些变化 ERAD的结果表明，钙离子与阳离子结合结构域的结合是 对于正常的ER加工α 1 Ib是必需的。这一假设将是 通过以下具体目的进行测试：（1）测试α 1 Ib亚基的正常成熟需要结构完整的阳离子结合的假设 域. (2)为了验证α 1 Ib-β 3的正常生物发生 受体复合物需要钙离子与α 11b阳离子结合 域. (3)鉴定与α 1 Ib相互作用的ER分子伴侣， 测试钙离子与α 1 Ib阳离子结合的假设， 影响与伴侣蛋白的相互作用。

DESCRIPTION (provided by applicant): The platelet integrin alpha-IIb-beta3 mediates platelet aggregation and plays a critical role in hemostasis. Patients without functional alphaIIb-beta3 receptors manifest in the bleeding disorder Glanzmann thrombasthenia (GT). The medical importance of alphalIb-beta3 is highlighted, by the ability of alphalIb-beta3 antagonists to prevent the ischemic complications of unstable angina and percutaneous coronary interventions. Some mutations in the alphalIb submit that result in GT have been shown to completely block maturational processing of alphalIb, causing the protein to be retained in the endoplasmic reticulum (ER). In particular, mutations in and around the four cation-binding domains of alpha1Ib universally result in ER retention. These specific cases of GT comprise a paradigm for agenetic disease caused by a conformational change in protein structure which results in abnormal ER processing, and ultimately results in ER retention and degradation. The alpha1Ib cation-binding domains have highly conserved hydrophobic residues that are required for the normal biogenesis of the receptor complex. Even conservative amino acid substitutions in these regions profoundly affects the level of alpha1Ib expression and degree of maturation. These data suggest that the conservative changes in the cation-binding domains are altering their structure, which affects their cation binding affinity. That these changes result in ERAD suggest that calcium binding to the cation-binding domains is essential for normal ER processing of alpha1Ib. This hypothesis will be tested by the following specific aims: (1) To test the hypothesis that normal maturation of the alpha1Ib subunit requires structurally intact cation binding domains. (2) To test the hypothesis that normal biogenesis of the alpha1Ib-beta3 receptor complex requires calcium binding to the alpha1lb cation-binding domains. (3) To identify ER chaperones that interact with alpha1Ib, and to test the hypothesis that calcium binding to the alpha1Ib cation-binding, affects interaction with chaperone proteins.