BIOCHEMISTRY OF UBIQUITIN-CONJUGATING ENZYMES

泛素结合酶的生物化学

• 批准号: 6520356
• 负责人: VINCENT CHAU
• 金额: $ 29.93万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6520356
• 关键词: endoplasmic reticulum; enzyme mechanism; enzyme model; enzyme substrate; human genetic material tag; ligase; membrane activity; myosins; protein degradation; protein localization; proteolysis; tissue /cell culture; ubiquitin

DESCRIPTION (adapted from applicant's abstract): ER-associated degradation refers to the process whereby membrane as well as lumenal proteins in the endoplasmic reticulum (ER) compartment are degraded by the cytosolic 26S proteasome. Proteins that are routed into this degradative pathway include proteins whose levels are subjected to regulated proteolysis as well as newly synthesized proteins that entered the ER but failed either to fold properly or to be assembled with their constituent protein partners. In several human hereditary diseases, extensive degradation of specific allelic variants results in the reduction or absence of such proteins in their destined compartment, leading to deficiency in function and disease symptoms. Examples of such allelic variants have been found with the CFTR protein in cystic fibrosis, alpha1-antitrypsin in childhood liver disease and adult emphysema, insulin receptor in type A insulin resistance, LDL receptor in familial hypercholesterolemia and in myeloperoxidase deficiency. While the role of ubiquitin-mediated proteolysis in the degradation of ER-associated proteins is well recognized, virtually nothing is known on the ubiquitination process of this pathway in mammalian cells. Such information is crucial to understand how the pathway could be regulated and to evaluate the potential of this pathway for therapeutic intervention. The principal investigator proposes here that ER-associated degradation in mammalian cells utilizes a similar cascade of reactions as in the yeast Saccharomyces cerevisiae, for which the identity of several protein participants of the ubiquitination process have been identified by genetic analysis. The goal will be to test this hypothesis with a model substrate system that offers the significant advantage of being amenable to biochemical analysis. To this end, the principal investigator has identified a set of human ubiquitin-conjugating enzymes and ubiquitin-protein ligases that are likely participants in this pathway. He expects that the biochemical analysis will provide important mechanistic insights and the prerequisite information for the evaluation of this pathway for potential therapeutic intervention.

描述（改编自申请人摘要）：er相关降解