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

University Of Southern California, Los Angeles CA

Investigators

Abstract

NONTECHNICAL SUMMARY The 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 SUMMARY The 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.