Genetic Analysis of HECT Ubiquitin Ligases

HECT 泛素连接酶的遗传分析

基本信息

批准号：
6806442
负责人：
BRIAN Patrick DOWNES
金额：
$ 4.89万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-01 至 2005-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6806442
关键词：
Arabidopsis enzyme mechanism enzyme structure isozymes ligase mutant plant genetics postdoctoral investigator proteasome protein degradation ubiquitin

项目摘要

DESCRIPTION (provided by applicant): The selective degradation of cellular proteins is essential for the growth development, and well being of all living organisms. The protein ubiquitin is an integral part of one major proteolytic pathway which is highly conserved in all eukaryotic species. The specific degradation of proteins by the ubiquitin-dependant proteolytic pathway involves two major recognition steps. In the first step, the protein to be degraded is recognized by a key enzyme in the pathway, the ubiquitin ligase, whereupon the targeted protein is covalently modified with multiple ubiquitins. In the second step, the ubiquitinated protein is recognized by the 26S proteasome and degraded. The importance of this proteolytic pathway is underscored by its function in such diverse processes as cell cycle progression, DNA repair, peroxisome biogenesis, antigen presentation, protein trafficking and the degradation of abnormal proteins. The fact that various diseases appear to block normal ubiquitin pathway function argues the need to study the pathway in order to discover new methods of treatments when the pathway fails. The study proposed here is to isolate and characterize mutants in one subfamily of ubiquitin ligases, the large monomeric HECTs, from the model genetic plant Arabidopsis thaliana. Given the remarkable conservation of the Ub/26S proteasome pathway in all eukaryotes, this will not only define the functions of HECT-E3s in plants but also help us understand their basic roles in the eukaryotic cell and in human health. Ultimately, the study will contribute new strategies to affect the pathway for medicinal benefit.

描述（由申请人提供）：细胞蛋白质的选择性降解对于所有生物体的生长发育和健康至关重要。蛋白质泛素是一种主要蛋白水解途径的组成部分，该途径在所有真核物种中高度保守。泛素依赖性蛋白水解途径对蛋白质的特异性降解涉及两个主要的识别步骤。第一步，待降解的蛋白质被该途径中的关键酶泛素连接酶识别，随后目标蛋白质被多个泛素共价修饰。第二步，泛素化蛋白被26S蛋白酶体识别并降解。这种蛋白水解途径的重要性因其在细胞周期进程、DNA 修复、过氧化物酶体生物发生、抗原呈递、蛋白质运输和异常蛋白质降解等不同过程中的功能而得到强调。各种疾病似乎会阻断正常的泛素通路功能，这一事实表明有必要研究该通路，以便在该通路失效时发现新的治疗方法。这里提出的研究是从模型遗传植物拟南芥中分离和表征泛素连接酶一个亚家族（大单体 HECT）中的突变体。鉴于所有真核生物中 Ub/26S 蛋白酶体途径的显着保守性，这不仅将定义 HECT-E3 在植物中的功能，而且有助于我们了解它们在真核细胞和人类健康中的基本作用。最终，该研究将提供新的策略来影响药用价值的途径。