Biophysical Society Conference | Tahoe 2022

Molecular Biophysics of Membranes

Wednesday Speaker Abstracts

TRPA1 – BIASED AGONISM AND STRUCTURAL MECHANISMS OF MODULATION Jun Chen 1 ; 1 Genentech, Biochemical Cellular Pharmacology, South San Francisco, CA, USA TRPA1, also known as wasabi receptor, is a chemonociceptor implicated in pain, neurogenic inflammation and respiratory diseases. Electrophilic agonists activate the channel through covalent modification of cysteine residues, but how non-covalent ligands activate and how antagonists block the channel remain poorly understood. By using electrophysiology, mutagenesis, and cryo-EM, we have determined binding sites and interaction mechanisms for several classes of TRPA1 agonists and antagonists. Furthermore, we demonstrate that agonists targeting the same channel protein, or even the same structural domains, can exert distinct biophysical, physiological and pharmacological consequences. Hence, we reveal biased agonism and modulation mechanisms, shedding insights on understanding TRPA1 function and guiding therapeutic development. IMPACT OF LIPID-MEMBRANE PROTEIN INTERACTIONS ON MEMBRANE PROTEIN STRUCTURE AND DYNAMICS Linda Columbus 1 ; 1 University of Virginia, Chemistry, Charlottesville, VA, USA The role of lipids and detergents in stabilizing membrane protein structure and dynamics as a solvent and through specific binding is not well understood. Much is now known about the partitioning of amino acids within the membrane in the context of membrane structure and synthesis, however, the energetics and molecular determinants of interactions between proteins and lipids (or membrane mimics) are largely unknown A few binding motifs for specific interactions such as a CARC or CRAC domain have been proposed and there is additional evidence for other specific interactions. Yet, a unifying principle (similar to soluble proteins and water) of how membrane proteins interact with and evolve with their solvent does not currently exist. Our laboratory aims to develop an understanding of how lipids stabilize membrane protein structure using membrane mimics that allow interactions to be controlled and titrated. Our current systems include a beta-barrel outer membrane protein, Opa, an inner membrane enzyme, LspA, a two transmembrane alpha-helical membrane protein, TM0026, and the alpha-helical leucine transporter, LeuT. I will present our latest work in determining how lipids and membrane mimics interact with these proteins to stabilize their structure, dynamics, and function.

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