Nanoscale Approaches to Understanding Membrane Protein Function

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Project Summary / Abstract Biological membranes are needed by all life forms. These lipid bilayers separate the inside and outside of the cell and provide the separation between internal compartments. As such, they are the site for cellular recognition and communication and provide the home to a host of proteins that mediate signaling, catalysis, the generation and transduction of energy and the import and export of molecules. Despite this central role in life, membranes and membrane proteins have often been difficult to study using the normal tools of biochemistry and molecular biology. Membrane proteins display altered activity or are inactive when removed from their native lipid environment. Likewise, revealing the fundamental molecular recognition events involved in forming complex multi-component architectures at the membrane surface requires new methodologies. Nanodiscs, self-assembled nanoscale lipid bilayers solubilized by an amphipathic scaffold protein developed in our laboratory, have served to enable multiple new discoveries in these arenas. Under continued MIRA support, we will use the Nanodisc system to provide novel biochemical and biophysical paths to the realization of the molecular mechanisms involved in signaling, hormone biosynthesis, drug metabolism, the epitaxial presentation of oligomeric viral antigens and the membrane proteins of the synaptic junction. Systems under investigation include: The human cytochrome P450 systems involved liver and adrenal metabolism; the Ras GTPases involved in cancer signaling; vinculin, a critical component in the control of cellular migration, the proteins of the synaptic junction that bind oligomeric peptides, the ability of Nanodiscs to order complex oligomeric surface antigens and the biophysics of Nanodisc assembly.