Cellular Functions of Plasma Membrane Organization by Eisosomes

描述（由申请人提供）：质膜是细胞的定义特征，并作为其与外部环境的界面。目前的模型表明，它是横向组织在不同的蛋白质和脂质组成的域，这是重要的有效编排的关键反应的运输和通信，例如参与内吞作用。然而，尽管在理解膜过程和结构方面取得了巨大进展，但质膜组织的生理功能尚不清楚。为了克服用于调查的复杂模型的局限性，我们将重点研究在酵母质膜组织。该模型系统在质膜中具有突出的蛋白质和脂质分离，并且适用于分子、生物化学、遗传和系统方法。在这个项目中，我们将利用我们的发现eisosomes，大蛋白复合物的质膜下，作为主要组织者在酵母质膜结构域。我们的目标是确定质膜组织的分子机制和细胞功能。我们假设，eisosomes组装成一个稳定的膜支架，在磷酸肌醇细胞生物学和内吞作用中发挥着重要作用。为了测试这个模型，我们将使用定向生物化学，结构生物学，细胞生物学实验，结合无偏见的分析工具，包括最先进的蛋白质组学和系统遗传学。通过解决这些质膜生物学的核心问题，并阐明膜组织的功能，通过eisosomes，我们将解决一个基本的细胞生物学问题。生物系统的显著特征，包括异质体蛋白质的结构，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。它们也可能对涉及质膜组织的广泛的人类病理学具有治疗意义。 公共卫生相关性：本研究将探讨异质体在质膜组织中的作用机制和生理功能，特别是在肌醇磷脂代谢和胞吞作用中的作用。通过解决这些问题，我们将揭示具有广泛意义的质膜生物学的基本原理。

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. PUBLIC HEALTH RELEVANCE: In the proposed project, we will determine the mechanism and physiological functions of plasma membrane organization by eisosomes, especially in phosphoinositides metabolism and endocytosis. By addressing these questions, we will reveal fundamental principles of plasma membrane biology with broad implications.