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Anaphase Promoting Complex-mediated Proteolysis

后期促进复合物介导的蛋白水解

基本信息

批准号：
7921266
负责人：
MARK J SOLOMON
金额：
$ 25.41万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2010-12-31
项目状态：
已结题

项目摘要

A key event in the progression through and exit from mitosis is the ubiquitin-dependent degradation of cyclins and other key proteins by the Anaphase Promoting Complex (ARC; also called the cyclosome).ARC substrates contain degradation motifs such as the Destruction Box and the KEN Box that are required for their ubiquitination and for their binding to the ARC activators, Cdc20 and Cdh1. Both motifs are required for efficient degradation, but either one alone suffices for binding to Cdhlp. We have proposed a pathway for the assembly of the APC-Cdhip-substrate complex in which APC-free Cdhlp first binds a substrate. Engagement of the substrate Destruction Box by Cdh1p stimulates the binding of Cdh1p to the ARC, presumably via a conformation change in Cdhlp. The current studies are aimed at furthering our understanding of APC-mediated protedlysis in budding yeast. In particular, we wish to identify novel ARC substrates, to understand how APC-Cdh1p/Cdc20p-substrate complexes are assembled and disassembled, and to understand how the spindle assembly checkpoint makes use of a KEN box to turn off APC-mediated proteolysis when chromosomes are not properly attached to the mitotic spindle. To achieve these goals, I propose the following Specific Aims: 1) To Identify Novel ARC Substrates. 2) To Assess the Generality of the APC-Cdhip-Substrate Assembly Pathway. 3) To Determine How D-Box Engagement Stimulates Cdh1p Binding to the ARC: 4) To Determine the Roles of Conserved Cdhlp Motifs and of Phosphcrylation in APC-Cdh1p-Substrate Assembly. 5) To Determine Whether Disassembly of the APC-Cdh1p-Substrate Complex is an Active Process. 6) To Determine the Function of the MadSp KEN Box in the Spindle Assembly Checkpoint. Degradation of key proteins is essential for cell division. Understanding this degradation is thus important for understanding normal cell proliferation, and how this process goes awry in disease states, particularly cancers.

有丝分裂进展和退出的一个关键事件是泛素依赖性降解细胞周期蛋白和其他关键蛋白由后期促进复合物（ARC；也称为环体）产生。ARC 底物含有降解基序，例如 Destruction Box 和 KEN Box，这是它们的泛素化以及与 ARC 激活剂 Cdc20 和 Cdh1 的结合。两个主题都是必需的为了有效降解，但单独任何一种都足以与 Cdhlp 结合。 We have proposed a pathway 用于组装 APC-Cdhip-底物复合物，其中不含 APC 的 Cdhlp 首先与底物结合。 Cdh1p 与底物破坏盒的接合刺激了 Cdh1p 与 ARC 的结合，大概是通过 Cdhlp 的构象变化。当前的研究旨在进一步加深我们对出芽过程中 APC 介导的蛋白溶解的理解。酵母。特别是，我们希望识别新型 ARC 基材，以了解如何 APC-Cdh1p/Cdc20p-基质复合物的组装和拆卸，并了解如何纺锤体组装检查点利用 KEN 盒来关闭 APC 介导的蛋白水解作用染色体未正确附着在有丝分裂纺锤体上。为了实现这些目标，我提出以下具体目标： 1) 识别新型 ARC 基材。 2) 评估 APC-Cdhip-基板组装途径的通用性。 3) 确定 D-Box 接合如何刺激 Cdh1p 与 ARC 结合： 4) 确定 APC-Cdh1p-底物中保守的 Cdhlp 基序和磷酸化的作用集会。 5) 确定APC-Cdh1p-底物复合物的分解是否是主动过程。 6) 确定MadSp KEN盒在主轴装配检查点中的功能。关键蛋白质的降解对于细胞分裂至关重要。因此，了解这种退化是对于理解正常细胞增殖以及这个过程在疾病状态下如何出错很重要，特别是癌症。