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制的核心组成部分，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。这些环形成一个中心空腔，其中未折叠的蛋白质以 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质的不同子集？我们假设异源寡聚复合物中的每个亚基的底物特异性不同。然而，这一假设仍未得到检验，因为人们对 TRiC-底物相互作用的性质知之甚少。该提案的目标是确定 TRiC 亚基中底物结合位点的位置，并阐明 TRiC 识别底物的机制。为此，我们将使用多学科方法来比较源自不同 TRiC 底物的基序如何与各个 TRiC 亚基结合。了解 TRiC 底物相互作用将揭示该伴侣蛋白促进蛋白质折叠的机制。这项工作将对开发新的治疗方法来改善与蛋白质错误折叠相关的疾病具有重要意义。 公共健康相关性：真核伴侣蛋白 TRiC 在许多重要细胞真核蛋白的成熟中发挥着重要作用，其功能丧失与神经退行性疾病和癌症等多种疾病有关。在所提出的实验中系统地剖析不同底物的伴侣蛋白-底物结合相互作用的结果将为这些病理学的治疗干预提供方向。