Linking membrane mechanics to membrane protein structure: Spatial organization and cooperative signaling of membrane proteins

技术概述材料研究部和分子与细胞生物科学部为该奖项提供资金。该奖项支持凝聚态物理、膜生物学和结构生物学交叉领域的理论研究。PI将探索细胞膜的空间组织和生物功能的物理原理。细胞膜是一个由脂质和膜蛋白组成的复杂组织，在许多细胞过程中起着不可或缺的作用。膜蛋白的功能特性并不完全由蛋白质结构决定，而是与周围的脂质双分子层协同作用。该项目的总体目标是将最近对膜组分分子结构的见解与连续弹性理论对细胞膜的粗粒度描述联系起来，从而在膜蛋白结构与细胞膜的组织和生物学功能之间提供一座桥梁。这些见解源于结构生物学的一些开创性突破。将膜力学与膜蛋白结构联系起来需要一种超越以往膜弹性模型的理论方法，这些模型主要集中在大分离时的圆柱形或锥形膜内含物。细胞膜是拥挤的，膜蛋白的大小和间距都在几纳米量级，并且发现膜蛋白表现出丰富多样的疏水形状。PI旨在开发细胞膜的通用弹性描述，允许从结构生物学中获得膜蛋白的复杂形状，并允许分析大量膜内含物之间的相互作用，这是与活细胞提供的拥挤膜环境最相关的实验场景。通过这个项目发展的一般理论概念将被用来解决三个模型系统中的具体生物学问题。首先，与各种报道的寡聚态和机械敏感离子通道结构相关的功能特征将以不同膜张力的通道门控曲线的形式进行预测。其次，膜蛋白多面体的最小能量形状——具有明确定义的多面体对称的多面体双层囊泡——将与组成脂质和膜蛋白的性质有关。第三，计划中的研究将探索膜介导的弹性相互作用对化学受体晶格的空间组织和合作信号传导的影响。这三个案例研究将使我们能够系统地探索膜组分的结构与细胞膜的空间组织和功能特性之间的关系。这将支持不同年龄段的教育活动，包括两名研究生，他们将(1)帮助指导本科生研究助理，(2)参加当地高中的外展活动，(3)与不同学术部门和机构的研究人员密切合作，(4)参与少数民族外展项目，(5)参与物理学和生物学界面新课程的开发和教学。该项目通过为市中心高中科学教师组织研讨会来支持洛杉矶中部的高中科学教育。材料研究部和分子与细胞生物科学部为本奖项提供资金。该项目探索了嵌入细胞膜的蛋白质生物学功能的物理原理，并支持凝聚态物理学、膜生物学和结构生物学交叉领域的研究。膜蛋白是一类丰富而重要的分子，在包括癌症和阿尔茨海默病在内的许多人类疾病中起着关键作用。近年来，在膜组分的结构解析和生物物理表征方面取得了一些重大突破。膜蛋白的生物学功能通常是由蛋白质结构与周围脂质双分子层（膜的主要组成部分）的性质之间的复杂相互作用决定的。这导致薄膜从其无扰动状态发生变形，这种变形可以用连续介质弹性理论定量描述，连续介质弹性理论在材料研究中得到了广泛的研究。本项目发展了膜的连续弹性理论，作为连接膜成分结构与体内细胞膜组织和生物功能的桥梁。在这个项目中发展的一般理论概念将被用来解决三个模型系统中的具体生物学问题。这些模型系统中的第一个涉及机械敏感离子通道，这是一种膜蛋白，可以对机械刺激做出反应，并构成触觉的基础。第二个模型系统涉及膜蛋白多面体，它已被提出作为膜蛋白结构研究的新工具。最后，第三个模型系统涉及化学感受器，例如，它构成了嗅觉的基础。化学感受器提供了一个被广泛研究的膜蛋白的例子，它能够在细胞膜上传递信号，并且最近已经显示出一种有趣的空间组织成规则的晶格结构。这三个案例研究代表了高实验兴趣的模型系统，并将允许系统地探索膜组分结构与细胞膜的空间组织和功能特性之间的关系。这个项目的科学目标是通过一系列的教育活动来补充的，这些活动将(1)支持研究生、本科生和高中生，(2)在物理和生物的界面上开发一门新的课程，(3)通过为市中心的高中科学教师组织讲习班来支持洛杉矶中部的高中科学教育。

TECHNICAL SUMMARYThe Division of Materials Research and the Division of Molecular and Cellular Biosciences contribute funds to this award. This award supports theoretical research at the intersection of condensed matter physics, membrane biology, and structural biology. The PI will explore the physical principles underlying the spatial organization and biological function of cell membranes. Cell membranes exhibit a complex organization of lipids and membrane proteins, and play an integral role in many cellular processes. The functional properties of membrane proteins are not purely determined by protein structure but, rather, membrane proteins act in concert with the surrounding lipid bilayer. The overall objective of this project is to relate recent insights into the molecular structure of membrane components, which have resulted from a number of seminal breakthroughs in structural biology, to the coarse-grained description of cell membranes in terms of continuum elasticity theory, thereby providing a bridge between the structure of membrane proteins and the organization and biological function of cell membranes.Linking membrane mechanics to membrane protein structure requires a theoretical approach going beyond previous elastic models of membranes, which have mostly focused on cylindrical or conical membrane inclusions at large separations. Cell membranes are crowded, with the size and spacing of membrane proteins both being of the order of a few nanometers, and membrane proteins are found to exhibit a rich variety of hydrophobic shapes. The PI aims to develop a versatile elastic description of cell membranes allowing for the complex shapes of membrane proteins obtained from structural biology, and permitting the analysis of interactions among a large number of membrane inclusions in close proximity, which is the experimental scenario most relevant for the crowded membrane environment provided by living cells. The general theoretical concepts developed through this project will be employed to address specific biological questions in three model systems. First, the functional characteristics associated with the various reported oligomeric states and structures of mechanosensitive ion channels will be predicted in the form of channel gating curves with varying membrane tension. Second, the minimum energy shapes of membrane protein polyhedra - faceted bilayer vesicles of well-defined polyhedral symmetry - will be related to the properties of the constituent lipids and membrane proteins. Third, the planned research will explore the impact of membrane-mediated elastic interactions on the spatial organization and cooperative signaling exhibited by chemoreceptor lattices. These three case studies will enable the systematic exploration of the relationship between the structure of membrane components and the spatial organization and functional properties of cell membranes.This supports educational activities across a range of age groups, including two graduate students who will (1) help to mentor undergraduate research assistants, (2) participate in outreach activities to local high schools, (3) collaborate closely with researchers across different academic departments and institutions, (4) engage in minority outreach programs, and (5) participate in the development and teaching of a new course at the interface of physics and biology. This project supports high school science education in central Los Angeles through the organization of workshops for inner-city high school science teachers.NONTECHNICAL SUMMARYThe Division of Materials Research and the Division of Molecular and Cellular Biosciences contribute funds to this award. This project explores the physical principles underlying the biological function of proteins embedded in cell membranes, and supports research at the intersection of condensed matter physics, membrane biology, and structural biology. Membrane proteins are an abundant and important class of molecules that play critical roles in many human diseases, including cancer and Alzheimer's. Recent years have seen several major breakthroughs in the structural elucidation and biophysical characterization of membrane components. The biological function of membrane proteins is generally determined by a complex interplay between protein structure and the properties of the surrounding lipid bilayer, a major component of the membrane. This leads to a deformation of the membrane from its unperturbed state which can be described quantitatively using the theory of continuum elasticity, which has been studied widely in the context of materials research. This project develops the continuum elasticity theory of membranes as a bridge connecting the structure of membrane components to the organization and biological function of cell membranes in vivo.The general theoretical concepts developed in this project will be employed to address specific biological questions in three model systems. The first of these model systems concerns mechanosensitive ion channels, which are membrane proteins that can respond to mechanical stimuli and constitute and form the basis for the sense of touch, for example. The second model system concerns membrane protein polyhedra, which have been proposed as a novel tool for the structural study of membrane proteins. Finally, the third model system concerns chemoreceptors which form the basis for the sense of smell, for example. Chemoreceptors provide a widely-studied example of membrane proteins able to transmit signals across cell membranes, and which have been shown recently to exhibit an intriguing spatial organization into regular lattice structures. These three case studies represent model systems of high experimental interest, and will allow the systematic exploration of the relationship between the structure of membrane components and the spatial organization and functional properties of cell membranes.The scientific goals of this project are complemented by a range of educational activities which will (1) support graduate, undergraduate, and high-school students, (2) lead to the development of a new course at the interface of physics and biology, and (3) support high school science education in central Los Angeles through the organization of workshops for inner-city high school science teachers.