Endoplasmic Reticulum (ER) Associated Degradation of Membrane Proteins in Yeast
酵母中内质网 (ER) 相关的膜蛋白降解
基本信息
- 批准号:7635717
- 负责人:
- 金额:$ 24.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-07-01 至 2010-05-31
- 项目状态:已结题
- 来源:
- 关键词:Applications GrantsBiogenesisCaucasiansCaucasoid RaceClinical TrialsComplementCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorDataDegradation PathwayDiseaseEndoplasmic ReticulumFutureGenesGoalsGrantHomologous GeneIn VitroInheritedLaboratoriesLinkMammalian CellMembraneMembrane ProteinsMolecular ChaperonesMolecular MachinesMutationNorth AmericaPathway interactionsPlayPolyubiquitinationProcessProteinsResearchRoleSystemTimeUbiquitinationYeastsbasedisease-causing mutationin vitro Assayin vivointerestmanmulticatalytic endopeptidase complexmutantnovelreconstitutionresearch studytool
项目摘要
DESCRIPTION (provided by applicant): Cystic fibrosis (CF) is the most common, inherited lethal disease in Caucasians in North America, and arises from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). The majority of disease-causing mutations block the maturation of this secreted protein, such that CFTR becomes trapped in the endoplasmic reticulum (ER) and is degraded by the proteasome. This process is referred to as ER associated degradation (ERAD), and >30 ERAD substrates from yeast to man have been identified, many of which are linked to specific diseases. ERAD substrate selection and targeting are catalyzed by molecular chaperones, but to date it has been difficult to define how and specifically at which step the chaperones impact CFTR degradation. Moreover, it has been challenging to define how a membrane protein, like CFTR, is delivered to the proteasome, and to identify uncharacterized genes required for maximal ERAD efficiency. To surmount existing technical barriers, the PI's laboratory established a yeast CFTR expression system and showed that unique chaperones play distinct roles during ERAD. To identify novel factors that catalyze ERAD, a micro-array "screen" was performed and a chaperone class with no previous connection to ERAD was found to facilitate CFTR degradation in yeast. In parallel with these studies, an in vitro system was established that recapitulates the polyubiquitination of CFTR and a CFTR homologue in yeast membranes. Based on these new data and tools, the goals of this grant application are to determine at which step in the CFTR degradation pathway known and newly identified chaperones function. And, for the first time, the requirements for substrate de-ubiquitination and proteasome targeting during ERAD will be investigated in a defined system. Importantly, data obtained from the in vitro assay will be complemented through in vivo studies in wild type and mutant yeast strains. This project reflects the PI's long-term interest in defining the molecular machines responsible for protein biogenesis in the ER, and this grant application constitutes the primary focus of ongoing research in the PI's laboratory. Finally, the results obtained from the experiments described in this application will direct future efforts to delineate the CFTR maturation pathway in mammalian cells, an effort that is vital as ongoing chaperone-based therapies to treat CF and other protein conformational diseases are entering clinical trials.
描述(由申请人提供):囊性纤维化(CF)是北美白种人中最常见的遗传性致命疾病,由囊性纤维化跨膜电导调节因子(CFTR)的突变引起。大多数致病突变会阻止这种分泌蛋白的成熟,从而导致 CFTR 被困在内质网 (ER) 中并被蛋白酶体降解。这一过程被称为 ER 相关降解 (ERAD),并且已鉴定出从酵母到人类的超过 30 种 ERAD 底物,其中许多与特定疾病有关。 ERAD 底物选择和靶向是由分子伴侣催化的,但迄今为止,很难确定伴侣如何以及具体在哪一步影响 CFTR 降解。此外,定义膜蛋白(如 CFTR)如何传递至蛋白酶体以及识别最大 ERAD 效率所需的未表征基因一直具有挑战性。为了克服现有的技术障碍,PI实验室建立了酵母CFTR表达系统,并表明独特的伴侣在ERAD过程中发挥着独特的作用。为了鉴定催化 ERAD 的新因子,进行了微阵列“筛选”,发现先前与 ERAD 没有联系的伴侣类可促进酵母中的 CFTR 降解。与这些研究同时进行的,还建立了一个体外系统来概括 CFTR 和 CFTR 同源物在酵母膜中的多泛素化。基于这些新数据和工具,本次拨款申请的目标是确定已知和新识别的伴侣分子在 CFTR 降解途径的哪一步发挥作用。而且,将首次在定义的系统中研究 ERAD 期间底物去泛素化和蛋白酶体靶向的要求。重要的是,从体外测定获得的数据将通过野生型和突变酵母菌株的体内研究得到补充。该项目反映了 PI 对定义负责 ER 中蛋白质生物发生的分子机器的长期兴趣,而这项拨款申请构成了 PI 实验室正在进行的研究的主要焦点。最后,从本申请中描述的实验中获得的结果将指导未来描绘哺乳动物细胞中 CFTR 成熟途径的努力,这一努力至关重要,因为正在进行的基于伴侣的治疗 CF 和其他蛋白质构象疾病的疗法正在进入临床试验。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JEFFREY L. BRODSKY其他文献
JEFFREY L. BRODSKY的其他文献
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