Principles of substrate recognition by the eukaryotic chaperonin TRiC/CCT

真核伴侣蛋白 TRiC/CCT 底物识别原理

• 批准号: 8003346
• 负责人: Lukasz A. Joachimiak
• 金额: $ 5.22万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8003346
• 关键词: Binding; Binding Sites; Complex; Development; Disease; Goals; Individual; Location; Malignant Neoplasms; Nature; Nerve Degeneration; Pathology; Play; Protein Binding; Proteins; Proteome; Role; Shapes; Substrate Interaction; Substrate Specificity; Therapeutic Intervention; Work; chaperonin; interdisciplinary approach; loss of function; novel therapeutic intervention; protein folding; protein misfolding; public health relevance; research study

DESCRIPTION (provided by applicant): The chaperonin TRiC/CCT is a central component of the eukaryotic protein folding machinery and is estimated to fold 5-10% of the eukaryotic proteome. TRiC assembles into a ring-shaped oligomeric complex that is comprised of two stacked rings each containing eight different subunits. The rings create a central cavity where unfolded proteins bind and fold in an ATP dependent manner. A fundamental question remains: how does TRiC recognize and fold a diverse subset of eukaryotic proteins? We hypothesize that each subunit in the hetero-oligomeric complex differs in substrate specificity. However, this hypothesis remains untested, as little is known about the nature of TRiC-substrate interactions. The goal of this proposal is to identify the location of the substrate binding sites in the TRiC subunits and elucidate the mechanisms underlying substrate recognition by TRiC. To this end, we will use a multidisciplinary approach to compare how motifs derived from different TRiC substrates bind to individual TRiC subunits. Understanding TRiC substrate interactions will reveal the mechanism by which this chaperonin facilitates protein folding. This work will have important implications for the development of novel therapeutic approaches to ameliorate diseases associated with protein misfolding. PUBLIC HEALTH RELEVANCE: The eukaryotic chaperonin TRiC plays a fundamental role in the maturation of many important cellular eukaryotic proteins, and its loss-of-function is associated with numerous diseases such as neurodegeneration and cancer. The results of systematically dissecting the chaperonin-substrate binding interactions for diverse substrates in the proposed experiments, will offer directions for therapeutic interventions in these pathologies.

描述（由申请人提供）：伴侣蛋白Tric/CCT是真核蛋白质折叠机械的核心组成部分，估计可折叠真核蛋白质组的5-10％。 Tric组装成一个环形寡聚复合物，该复合物由两个堆叠环组成，每个环包含八个不同的亚基。环会产生一个中央空腔，其中展开的蛋白质以ATP依赖性方式结合和折叠。一个基本问题仍然存在：Tric如何识别和折叠真核蛋白的各种子集？我们假设异源络合物中的每个亚基在底物特异性方面有所不同。然而，该假设仍未经过测试，对三叶基层相互作用的性质知之甚少。该提案的目的是确定底物结合位点在三分线亚基中的位置，并阐明Tric通过底物识别的机制。为此，我们将使用一种多学科的方法来比较来自不同的三分线底物与单个三分线亚基的基序。理解三底物相互作用将揭示该伴侣蛋白促进蛋白质折叠的机制。这项工作将对发展与蛋白质错误折叠相关的新型治疗方法的发展具有重要意义。 公共卫生相关性：真核伴侣蛋白Tric在许多重要的细胞真核蛋白的成熟中起着基本作用，其功能丧失与许多疾病（如神经变性和癌症）有关。在拟议的实验中，系统剖析不同底物的伴侣蛋白 - 基底结合相互作用的结果将为这些病理中的治疗干预提供方向。