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-β3介导血小板聚集并发挥作用 在止血中起关键作用。缺乏功能性AlphaIIb-Beta3的患者 受体在出血性疾病Glanzmann血栓减少症(GT)中表现出来。 AlphalIb-beta3的医学重要性通过以下能力得到强调： αIb-β3拮抗剂预防不稳定型心肌缺血并发症 心绞痛和经皮冠状动脉介入治疗。基因中的一些突变 AlphalIb在>中提交结果已显示为完全阻止 AlphalIb的成熟处理，使蛋白质保留在 内质网(ER)。特别是，这四个基因及其周围的突变 Alpha1Ib的阳离子结合域普遍导致内质网滞留。这些 GT的特定病例构成了一种由一种 蛋白质结构的构象变化导致内质网异常 处理，并最终导致内质网滞留和降解。这个 Alpha1Ib阳离子结合区具有高度保守的疏水残基 这是受体复合体正常生物发生所必需的。连 这些区域的保守氨基酸替换深刻地影响着 α1Ib的表达水平和成熟度。这些数据表明 阳离子结合域的保守变化正在改变它们的 结构，这会影响它们的阳离子结合亲和力。这些变化 ERAD的结果表明，与阳离子结合结构域的钙结合是 对alpha1Ib的正常内质网加工是必不可少的。这一假设将是 通过以下特定目的进行测试：(1)测试Alpha1Ib亚基的正常成熟需要结构完整的阳离子结合的假设 域名。(2)检验α1Ib-β3的正常生物发生假说 受体复合体需要与Alpha1lb阳离子结合的钙结合 域名。(3)鉴定与α1Ib相互作用的内质网伴侣 测试钙与Alpha1b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.