The functional organization of mammalian membranes

University Of Virginia, Charlottesville VA

Investigators

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Abstract

Project Summary Our laboratory investigates the functional organization of mammalian membranes to generate mechanistic insights into the connections between lipid composition, membrane structure, and cell physiology. Membranes host a major fraction of all cellular bioactivity, orchestrating myriad simultaneous, parallel tasks. This functionality is enabled by the remarkable complexity and diversity of mammalian lipidomes, which give rise to a unique combination of biophysical phenotypes, including membrane fluidity, tension, curvature, and lateral compartmentalization. We aim for a predictive understanding of how lipidome features determine membrane properties, and how these in turn regulate cell functions. Recently, my lab has revealed the surprising complexity, diversity, and plasticity of mammalian lipodomes and have made insights into how these determine the lateral and transbilayer organization of cell membranes. These connections have revealed strategies for rational engineering of membrane phenotypes to guide cell signaling and behavior. Our current and future research aims to answer the following broad questions: (1) why are living membranes asymmetric? How is loss of lipid asymmetry functionalized? (2) what is the lateral organization of mammalian plasma membranes (PMs), how is it regulated, and what is its purpose? (3) how are complex lipidomes regulated and what are the pathological consequences of dysregulation? These questions have become accessible through methodological advances in high-throughput lipidomics, quantitative advanced microscopy, and spatially resolved fluorescence spectroscopy. For example, we determined the asymmetric composition of mammalian PMs and its biophysical and structural consequences. Although such asymmetry appears to be a universal design principle for Eukaryote membranes, its selective advantages are unknown. We are exploring how membrane physical properties are coupled across asymmetric leaflets and the physiological purpose of lipid asymmetry. We found that local, transient release of membrane asymmetry accompanies immune cell activation and is necessary for optimal signaling: however, how transient lipid scrambling is regulated and functionalized is unknown. In parallel, we defined structural features responsible for protein association with ordered membrane domains and how such domains are involved in membrane traffic, protein sorting, and signal transduction. Our experimental and computational framework allows us to investigate the structural codes for protein affinity for ordered domains and how protein association with membrane domains facilitates their localization and function. Finally, we have characterized the remarkable plasticity of mammalian membranes and their susceptibility to dietary fatty acids and characterized the effects of external inputs on membrane properties and cell function. However, how cells maintain membrane homeostasis in response to continuous challenges from dietary and other inputs is poorly understood. Addressing these questions will advance our understanding of the functional role of membrane organization across the tree of life.