Cellular Functions of Plasma Membrane Organization by Eisosomes

Eisosomes 组织质膜的细胞功能

• 批准号: 8776315
• 负责人: Tobias C Walther
• 金额: $ 30.69万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8776315
• 关键词: ATP phosphohydrolase; Actins; Address; Architecture; Area; Binding; Biochemical; Biochemical Genetics; Biological Models; Buffers; Cell membrane; Cell physiology; Cells; Cellular biology; Communication; Complex; Comprehension; Data; Data Set; Endocytosis; Environment; Genes; Genetic; Higher Order Chromatin Structure; Human Pathology; In Vitro; Investigation; Laboratories; Link; Lipid Binding; Lipids; Measures; Mediating; Membrane; Membrane Biology; Metabolism; Modeling; Molecular; Pathway interactions; Phenotype; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Physiological; Play; Process; Property; Proteins; Proteomics; Recruitment Activity; Research; Role; Specificity; Structure; System; Testing; Therapeutic; Transport Reaction; Yeasts; analytical tool; biological systems; membrane reconstitution; mutant; protein complex; reconstitution; research study; scaffold; segregation; structural biology; synaptojanin

DESCRIPTION (provided by applicant): The plasma membrane is the defining feature of cells and serves as their interface with the external environment. Current models posit that it is laterally organized in domains of distinct protein and lipid composition that are important for the efficient orchestration of key reactions of transport and communication, for example involved in endocytosis. However, despite tremendous advances in the comprehension of membrane processes and structure, physiological functions of plasma membrane organization are not yet clear. To overcome limitations of complex models used for investigation, we will focus on studying plasma membrane organization in yeast. This model system has prominent protein and lipid segregation in the plasma membrane and is amenable to molecular, biochemical, genetic and systems approaches. In this project, we will capitalize on our discovery of eisosomes, large protein complexes underlying the plasma membrane, as principal organizers plasma membrane domains in yeast. We aim to define the molecular mechanisms and cellular functions of plasma membrane organization. We hypothesize that eisosomes assemble into a stable membrane scaffold that plays fundamental roles in phosphoinositide cell biology and endocytosis. To test this model, we will use directed biochemical, structural biology, cell biology experiments combined with unbiased analytical tools, including state-of-the-art proteomics and systematic genetics. By tackling these central questions on plasma membrane biology and elucidating the function of membrane organization by eisosomes, we will address a fundamental cell biology problem. Salient features of biological systems, including the structure of eisosome proteins are most often evolutionary conserved. Our findings will therefore likely have a broad impact on membrane research. They might also have therapeutic implications for a wide range of human pathologies where plasma membrane organization is implicated.

描述（由申请人提供）：质膜是细胞的决定性特征，并充当细胞与外部环境的界面。目前的模型认为，它在不同的蛋白质和脂质组成的域中横向组织，这对于有效协调运输和通讯的关键反应（例如参与内吞作用）非常重要。然而，尽管对膜过程和结构的理解取得了巨大进步，但质膜组织的生理功能尚不清楚。为了克服用于研究的复杂模型的局限性，我们将重点研究酵母的质膜组织。该模型系统在质膜中具有显着的蛋白质和脂质分离，并且适合分子、生化、遗传和系统方法。在这个项目中，我们将利用我们对胞质体（质膜下方的大型蛋白质复合物）的发现，作为酵母中质膜结构域的主要组织者。我们的目标是定义质膜组织的分子机制和细胞功能。我们假设内切体组装成稳定的膜支架，在磷酸肌醇细胞生物学和内吞作用中发挥基本作用。为了测试这个模型，我们将使用定向生化、结构生物学、细胞生物学实验与公正的分析工具相结合，包括最先进的蛋白质组学和系统遗传学。通过解决质膜生物学的这些核心问题并阐明胞质体的膜组织功能，我们将解决一个基本的细胞生物学问题。生物系统的显着特征，包括胞质体蛋白的结构，通常是进化保守的。因此，我们的发现可能会对膜研究产生广泛的影响。它们还可能对涉及质膜组织的多种人类病理学具有治疗意义。

项目成果

The GARP complex is required for cellular sphingolipid homeostasis.

• DOI: 10.7554/elife.08712
• 发表时间: 2015-09-10
• 期刊: eLife
• 影响因子: 7.7
• 作者: Fröhlich F;Petit C;Kory N;Christiano R;Hannibal-Bach HK;Graham M;Liu X;Ejsing CS;Farese RV;Walther TC
• 通讯作者: Walther TC

Global proteome turnover analyses of the Yeasts S. cerevisiae and S. pombe.

• DOI: 10.1016/j.celrep.2014.10.065
• 发表时间: 2014-12-11
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Christiano R;Nagaraj N;Fröhlich F;Walther TC
• 通讯作者: Walther TC