CAREER: Fluctuations, Shape, and Collective Function of Membrane Protein Lattices

非技术性总结数学和物理科学局的材料研究部和生物科学局的分子和细胞生物科学部共同资助这一职业奖项。它支持蛋白质和细胞膜的理论研究和教育。蛋白质是生命的分子主力。生物学的一个中心范式认为，蛋白质的生物学功能源于它们的分子结构。细胞膜传统上被认为是被动的脂质双层包膜，分散的膜蛋白在其中随机扩散，就像冰山漂浮在海洋中一样。膜蛋白结构完全决定了细胞膜如何控制细胞与其环境之间以及细胞内不同隔室之间的分子和信号流动，这对所有生物都是必不可少的。随着细胞膜结构定量表征的开创性实验突破，这个细胞膜模型经历了根本性的修改，揭示了膜蛋白的层次组织和协作功能的复杂系统；细胞膜功能的许多关键方面不能通过只考虑单一的膜蛋白来理解，而是从蛋白质结构、脂双层-蛋白质相互作用、膜蛋白到蛋白质晶格的超分子组织和膜形状的集体属性中产生。这个项目的基本研究目标是将关于细胞膜的结构、组织、形状和集体功能的实验数据整合到对细胞膜的物理理解中，从而定量地理解细胞膜在协同信号、离子交换和细胞形状调节中的一些基本生物学功能。PI将建立在以前在凝聚态物理和材料科学方面取得巨大成功的理论框架和方法的基础上。在与实验小组的密切合作下，将为具有广泛生物学意义的实验模型系统测试和改进本项目中设想的一般细胞膜物理模型。本项目中的跨学科研究活动将通过为高中科学教师组织研讨会和开发生物物理案例研究来紧密结合物理和生物学界面上的教学活动，并在高中水平上展示物理如何对生物学产生定量的见解。该项目还将为研究生和博士后学者提供一系列机会，以参与物理学和生物学交界处的跨学科研究和教学活动。技术总结数学和物理科学局的材料研究部和生物科学局的分子和细胞生物科学部共同资助这一职业奖项。它支持蛋白质和细胞膜的理论研究和教育。细胞膜是生命的基本标志之一。细胞膜的许多生物学功能依赖于相互作用的膜蛋白晶格的集体性质。该项目的主要研究目标是基于凝聚态物理和材料科学的方法，建立一个新的理论框架，以捕捉细胞膜中观察到的膜蛋白晶格的波动、形状和集体功能的物理机制。首席研究员和他的团队将与实验小组密切合作，测试和完善这一完整和外周膜蛋白的理论框架，从而通过两个部分发现和描述细胞膜关键生物学功能的一般物理原理：(1)完整膜蛋白对细胞与环境之间的分子和信号交换至关重要。完整膜蛋白的功能通常受脂双层机械性质和协同作用的调节，例如机械敏感离子通道和化学感受器。基于这两个模型系统，PI旨在开发一个通用的物理理论，该理论可以预测双层-蛋白质相互作用、脂质异质性和热波动如何与细胞膜中观察到的完整膜蛋白晶格的集体功能有关。这将提供将双层-蛋白质相互作用的经典理论与完整的膜蛋白晶格的结构和集体功能的体内数据联系起来所需的理论工具。(2)外周膜蛋白允许细胞调节膜形状，这对许多细胞过程是必不可少的。外周膜蛋白如何相互作用以产生膜形状的大规模转变在很大程度上仍不清楚。最近对N-bar蛋白内亲和素的实验表明，在脂质双层-内亲和素相互作用中发生了结构转换，产生了不同的膜形状。在这些实验的基础上，PI计划建立一个普遍的理论，该理论可以捕捉到亲内素诱导的脂双层变形的物理机制，以及亲内素晶格的结构和形状。这项活动旨在为定量了解双层-蛋白质相互作用如何在内吞作用和其他基本生物过程中产生膜形状的转变提供基础。本项目中进行的跨学科研究将为一系列跨学科教育和推广活动提供信息，这些活动将在高中、本科和研究生教育水平上开发整合物理和生物学的新教学方法和材料。

NONTECHNICAL SUMMARYThe Division of Materials Research in the Mathematical and Physical Sciences Directorate and the Molecular and Cellular Biosciences Division in the Biological Sciences Directorate co-fund this CAREER award. It supports theoretical research and education on proteins and cellular membranes. Proteins are the molecular workhorses of life. A central paradigm of biology holds that the biological function of proteins follows from their molecular structure. Cell membranes have traditionally been conceptualized as passive lipid bilayer envelopes in which dispersed membrane proteins diffuse randomly, much like icebergs float in the ocean. Membrane protein structure fully determines how cell membranes control the flow of molecules and signals between cells and their environment, as well as between different intracellular compartments, which is essential to all organisms.Following seminal experimental breakthroughs in the quantitative characterization of cell membrane structure, this model of cell membranes has been undergoing a radical revision, revealing a complex system of hierarchical layers of organization and cooperative function of membrane proteins; many of the key aspects of cell membrane function cannot be understood by considering only single membrane proteins but, instead, emerge from the collective properties of protein structure, lipid bilayer-protein interactions, the supramolecular organization of membrane proteins into protein lattices, and membrane shape.The fundamental research goal of this project is to integrate experimental data on the structure, organization, shape, and collective function of cell membranes into a physical understanding of cell membranes across length and time scales leading to a quantitative understanding of some of the essential biological functions of cell membranes in cooperative signaling, ion exchange, and regulation of cell shape. The PI will build on theoretical frameworks and approaches employed previously with great success in the context of condensed matter physics and materials science. In close collaboration with experimental groups, the general physical models of cell membranes conceived in this project will be tested and refined for experimental model systems of wide biological significance.The interdisciplinary research activities in this project will be closely integrated with teaching activities at the interface of physics and biology through the organization of workshops for high school science teachers, and the development of case studies in biological physics showing at the high school level how physics can yield quantitative insights into biology. This project will also provide a range of opportunities for graduate students and postdoctoral scholars to participate in interdisciplinary research and teaching activities at the interface of physics and biology.TECHNICAL SUMMARYThe Division of Materials Research in the Mathematical and Physical Sciences Directorate and the Molecular and Cellular Biosciences Division in the Biological Sciences Directorate co-fund this CAREER award. It supports theoretical research and education on proteins and cellular membranes. Cell membranes are one of the fundamental hallmarks of life. For many of their biological functions, cell membranes rely on the collective properties of lattices of interacting membrane proteins. The primary research objective of this project is to build, based on methods from condensed matter physics and materials science, a novel theoretical framework which captures the physical mechanisms underlying the fluctuations, shape, and collective function of membrane protein lattices observed in cell membranes. The principal investigator and his team will closely collaborate with experimental groups to test and refine this theoretical framework for both integral and peripheral membrane proteins, and to thereby discover and describe the general physical principles underlying key biological functions of cell membranes through two parts:(1) Integral membrane proteins are crucial for the exchange of molecules and signals between cells and their environment. The function of integral membrane proteins is often regulated by lipid bilayer mechanical properties and cooperative interactions, as exemplified by mechanosensitive ion channels and chemoreceptors. Based on these two model systems, the PI aims to develop a general physical theory which can predict how bilayer-protein interactions, lipid heterogeneity, and thermal fluctuations relate to the collective functions of integral membrane protein lattices observed in cell membranes. This will provide theoretical tools needed to connect the classic theory of bilayer-protein interactions to in vivo data on the architecture and collective function of integral membrane protein lattices.(2) Peripheral membrane proteins allow cells to regulate membrane shape, which is essential for many cellular processes. It remains largely unknown how peripheral membrane proteins interact to produce large-scale transitions in membrane shape. Recent experiments on the N-BAR protein endophilin have revealed a structural switch in lipid bilayer-endophilin interactions which generates distinct membrane shapes. Based on these experiments, the PI plans to establish a general theory which captures the physical mechanisms underlying endophilin-induced lipid bilayer deformations, and the architecture and shape of endophilin lattices. This activity is aimed to provide the foundation for a quantitative understanding of how bilayer-protein interactions are regulated to produce transitions in membrane shape during endocytosis and other fundamental biological processes.The interdisciplinary research carried out in this project will inform a range of interdisciplinary education and outreach activities, which will develop novel teaching approaches and materials integrating physics and biology at the level of high school, undergraduate, and graduate education.