Biophysical Society Conference | Tahoe 2022

Molecular Biophysics of Membranes

Tuesday Speaker Abstracts

MEMBRANE CURVATURE AS A REGULATOR OF GPCR ORGANIZATION AT THE PLASMA MEMBRANE Dimitrios Stamou 1 ; 1 University of Copenhagen, Copenhagen, Denmark The plasma membrane (PM) is constantly subject to forces exerted by the cell and the surrounding tissue environment. However, intriguingly most of the PM surface area remains nearly flat, displaying only gentle undulations of extremely shallow curvature (< 1µm-1). Nevertheless, this prevalent spatial PM phenotype and its biological role have been disregarded to date. Here we used a combination of 1) super-resolved 3D live-cell imaging, 2) high throughput mechanical cell-curvature modulation, and 3) molecular field theory to investigate the influence of extremely shallow curvature on the spatial organization of G protein-coupled receptors (GPCRs) at the PM.Our work revealed GPCR energetic coupling to extremely shallow PM curvature (< 1 µm-1) as the dominant, necessary, and sufficient molecular mechanism of GPCR spatiotemporal organization. Shallow-curvature coupling is GPCR-specific and cell- specific and is regulated by ligands. However, it is based on universal physicochemical principles and should influence the spatial organization of PM-associated proteins in general. This novel mechanism elucidates why and how any (biomechanical or biochemical) stimulus that modulates PM-morphology can regulate protein organization and thus likely signaling at the PM. LIPIDS AND DIVALENT CATIONS AS REGULATORS OF BILAYER INSERTION OF PHLIP AND BCL-2 PROTEINS Alexey Ladokhin 1 ; 1 University of Kansas, Kansas City, KS, USA Every tissue, cell, and organelle has specific electrochemical properties resulting from differences in concentrations of protons, small ions, and charged macromolecules. Delivering proteins to these different environments can trigger functionally relevant structural rearrangements, which we refer to as conformational switching. A notable example is the transition of specific soluble proteins into lipid membranes. This phenomenon is prominent in many physiological and pathogenic processes, including the regulation of apoptosis by the Bcl-2 family of proteins, critical for cancer treatment. Our ability to target or manipulate these processes can be beneficial for human health. For example, membrane insertion of the pH Low Insertion Peptide (pHLIP) has recently been used to target drugs to cancer cells. While these processes are of fundamental biomedical importance, basic knowledge of the mechanism of conformational switching is often lacking, impeding our ability to predict protein-lipid interactions under physiological conditions. Here we present our progress applying various experimental and computational approaches in deciphering complex interactions on membrane interfaces and establishing the role of lipid composition and divalent cations (i.e, Ca2+ and Mg2+) in modulating important physiological processes.

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