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Elucidating the contributions of ubiquitin ligase complexes to endoplasmic reticulum associated degradation (ERAD)

阐明泛素连接酶复合物对内质网相关降解 (ERAD) 的贡献

基本信息

批准号：
MR/L001209/1
负责人：
John Christianson
金额：
$ 40.02万
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FL001209%2F1
关键词：
Elucidating contributions ubiquitin ligase complexes

项目摘要

Proteins are the molecular machines of cells, performing a wide range of essential functions. A broad range of inherited human diseases can be traced back to single proteins that do not fold correctly. A change in the genetic code results in a protein that is unable to reach the correct 3-dimensional structure necessary to function. Other disorders are associated with conditions within cells that are unsuitable for proteins in general to fold correctly. For those proteins that are secreted or expressed on the surface of cells, protein folding occurs in the intracellular compartment known as the endoplasmic reticulum (ER). Within the ER, each protein is evaluated by quality control mechanisms that decide whether it's folded correctly. When proteins misfold, a complex remediation scheme is engaged which removes those forms from the ER and destroys them. Collectively, this mechanism is known as ER-associated degradation (ERAD). As cell surface and secreted proteins represent approximately 30% of all the human proteins made, distinguishing and degrading such a wide range of potentially misfolded proteins presents a significant challenge. ERAD uses a network of interconnected factors able to identify, target, deliver and degrade non-native proteins with various configurations. A central component in this scheme is the family of ubiquitin ligases embedded in the ER membrane. One example is Hrd1, which forms nexuses of ERAD activity by scaffolding different accessory factors on both sides of the ER membrane. This MRC project aims to characterise both the composition and organisation of Hrd1-containing complexes and to ascertain the contributions that the entire family of ER-resident ubiquitin ligases make to ERAD. The benefits of the proposed research will be to advance our understanding of how misfolded proteins are degraded in cells, and how this fundamental mechanism alleviates cellular stress that is the hallmark of many diseases. Our current view of ERAD has been based on a limited analysis of individual components and substrates. The proposed research aims to advance this picture by 1) characterising in detail, the functional Hrd1 complexes the carry out ERAD, 2) using a proven isolation strategy and mass spectrometry to characterise other ER-resident ubiquitin ligase complexes that participate in ERAD and 3) determining how cells use expression of the different ERAD components to respond to stress. As the number of diseases linked to protein misfolding grows, it is anticipated that the comprehensive analysis proposed here will advance our understanding of how these conditions may arise. Moreover, this study may help direct efforts to devise novel and alternative therapeutic strategies for the treatment of disorders of associated with protein misfolding and trafficking, such as cystic fibrosis and alpha1-antitrypsin deficiency.

蛋白质是细胞的分子机器，执行广泛的基本功能。广泛的人类遗传疾病可以追溯到单个不能正确折叠的蛋白质。遗传密码的改变导致蛋白质无法达到正常运作所必需的正确的三维结构。其他疾病与细胞内不适合蛋白质正常折叠的条件有关。对于那些在细胞表面分泌或表达的蛋白质，蛋白质折叠发生在称为内质网（ER）的细胞内。在内质网内，每个蛋白质都通过质量控制机制进行评估，以决定其折叠是否正确。当蛋白质错误折叠时，一个复杂的修复方案就会参与进来，将这些形式从内质网中移除并破坏它们。总的来说，这种机制被称为er相关降解（ERAD）。由于细胞表面和分泌的蛋白质约占所有人类蛋白质的30%，因此区分和降解如此广泛的潜在错误折叠蛋白质是一项重大挑战。ERAD使用一个相互关联的因子网络，能够识别、靶向、传递和降解各种结构的非天然蛋白质。该方案的核心组成部分是嵌入内质网膜的泛素连接酶家族。一个例子是Hrd1，它通过在内质网膜两侧架起不同的辅助因子形成ERAD活性的纽带。这个MRC项目旨在描述含hrd1复合物的组成和组织，并确定整个er驻留泛素连接酶家族对ERAD的贡献。这项提议的研究的好处将是促进我们对细胞中错误折叠蛋白质如何降解的理解，以及这种基本机制如何减轻许多疾病的标志细胞应激。我们目前对ERAD的看法是基于对单个组件和基板的有限分析。本研究旨在通过以下途径推进这一图景：1)详细描述执行ERAD的功能性Hrd1复合物；2)使用经过验证的分离策略和质谱分析来表征参与ERAD的其他ER-resident泛素连接酶复合物；3)确定细胞如何使用不同ERAD组分的表达来应对应激。随着与蛋白质错误折叠相关的疾病数量的增加，预计本文提出的综合分析将促进我们对这些疾病如何出现的理解。此外，这项研究可能有助于设计新的替代治疗策略，用于治疗与蛋白质错误折叠和运输相关的疾病，如囊性纤维化和α - 1抗胰蛋白酶缺乏症。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cleaning up in the endoplasmic reticulum: ubiquitin in charge.

DOI：
10.1038/nsmb.2793
发表时间：
2014-04
期刊：
NATURE STRUCTURAL & MOLECULAR BIOLOGY
影响因子：
16.8
作者：
Christianson, John C.;Ye, Yihong
通讯作者：
Ye, Yihong

The Unfolded Protein Response Triggers Site-Specific Regulatory Ubiquitylation of 40S Ribosomal Proteins.

DOI：
10.1016/j.molcel.2015.04.026
发表时间：
2015-07-02
期刊：
MOLECULAR CELL
影响因子：
16
作者：
Higgins, Renee;Gendron, Joshua M.;Rising, Lisa;Mak, Raymond;Webb, Kristofor;Kaiser, Stephen E.;Zuzow, Nathan;Riviere, Paul;Yang, Bing;Fenech, Emma;Tang, Xin;Lindsay, Scott A.;Christianson, John C.;Hampton, Randolph Y.;Wasserman, Steven A.;Bennett, Eric J.
通讯作者：
Bennett, Eric J.

The ER membrane protein complex is a transmembrane domain insertase.

ER膜蛋白复合物是跨膜结构域插入酶。