Designer nanodiscs to probe and reprogram membrane biology

Abstract Life originates from the enfolding of critical cellular activities by water-impermeable membrane structures. This compartmentalization is vital to maintain the identity and function of all cells and most organelles. However, the physical barrier of cell membranes also necessitates the development of sophisticated intercellular signaling pathways, ensuring precise coordination of distinct cellular activities across an organism’s various types of cells and tissues. In most cases, these signaling events are mediated by the collective interaction of diverse molecules, ranging from ions, metabolites, and lipids to secreted peptides, proteins, and membrane-embedded protein complexes. Intrigued by the fascinating precision and function of intercellular signaling in the maintenance of homeostasis, my laboratory investigates the operating principle of membrane biology underlying the starting point of cell-cell interactions and communication. Our overarching goal is to establish the connection between the structural dynamics of membrane protein-lipid interactions and the function of cell physiology. To this end, we have and will continue to develop the next-generation nanodisc toolbox that can bypass many limitations of traditional approaches for the characterization of membrane proteins, thereby opening up windows of new opportunities to access the membrane biochemical space unattainable in previous studies. With these powerful tools in hand, we seek to advance our understanding of membrane protein-lipid interactions essential for human health. Specifically, we will focus on interrogating how cell membranes regulate the structure, function and dynamics of proteins that drive membrane fusion, exosome secretion, and pore formation. Together, the proposed study will not only generate novel insights into the molecular mechanism of cell-cell interactions and communication, but also will bring about useful reagents to probe and reprogram fundamental signaling events at the cell surface.