The Interplay Between Membrane Structure and Protein Interactions

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Protein-membrane interactions are key events in processes as diverse as immunology and neurobiology, as they are the means by which information flows across the cell membrane. Thus protein-membrane interactions are the key to intercellular communication in multicellular organisms. While much work has been done to define what features of membrane -binding proteins confer specificity for their targets, the role of membrane lipid composition in these highly precise interactions is less well understood. In this research project, the PI will develop a comprehensive framework for understanding how the properties of the membrane impact protein-lipid recognition events. The complexity of the systems to be studied requires a truly multidisciplinary approach. With techniques and ideas adapted from molecular immunology, neurobiology, membrane physical chemistry, and interfacial X-ray scattering, this program will provide a unique training opportunity for the next generation of interdisciplinary scientists. Research opportunities will extend to qualified high school and undergraduate students. Concepts in interdisciplinary science will be brought to school children through the outreach activity “Physics with a Bang!” Regulation of protein-membrane interactions is governed in part by the specificity of peripheral membrane proteins for specific lipids. However, there appears to be a diverse landscape of parameters encoded into membranes that is dynamically controlled by the cell, offering distinct but correlated avenues to affect protein binding to membranes and subsequent functions. The work will address two fundamental questions: (1) How is information embedded in the composition and structure of lipid membranes properly recognized and distinguished by peripheral membrane-binding proteins? and (2) What is the relationship between membrane curvature and membrane tension in determining the binding behavior and subsequent function of proteins traditionally thought to be membrane curvature-sensing? For the former goal, the PI will largely focus on proteins that recognize phosphatidylserine phospholipids in the outer leaflet. For the latter goal, interactions with proteins that utilize amphipathic alpha helical motifs such as those found in alpha-synuclein will be studied. It is hypothesized that both classes of proteins employ sensitivity to differences in membrane properties and geometry to mediate their differential recognition properties. Thus, the primary focus of this research is to establish such sensitivities of their binding to fundamental physiochemical membrane parameters.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.