Physical Chemistry Seminar: Molecular Mechanisms of Phospholipid Scrambling by TMEM16 Proteins

When

4 – 5 p.m., May 1, 2023

Presenter:

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Khelashvili_Photo

Professor George Khelashvili, Assistant Professor of Physiology and Biophysics, Weill Cornell Medicine Department of Physiology & Biophysics, Cornell University

Abstract:

TMEM16 protein family members function as Ca2+-dependent phospholipid scramblases in cell membranes. Recent discoveries about functional mechanisms of TMEM16 proteins have illuminated the dual role of the membrane as both the substrate and a mechanistically responsive environment in the wide range of physiological processes and genetic disorders in which they are implicated. Still, some fundamental structure-function relations for many TMEM16 homologues remain unresolved. A key example is the conundrum posed by the apparent divergence in functional mechanisms between different TMEM16 homologs: it is not clear whether scrambling requires a Ca2+-driven global conformational rearrangement to open a translocation pathway for lipids (as shown for fungal nhTMEM16 PLS and for the human TMEM16K), or if it can occur outside a closed pathway (as suggested for the mouse TMEM16F, mTMEM16F). To distinguish between these mechanisms and to resolve whether TMEM16 scramblases function according to a common paradigm, we have been conducting extensive (hundreds of microsecond timescale) ensemble atomistic molecular dynamics (MD) simulations of various TMEM16 homologs. Combined with functional experiments, analysis of the accumulating MD data with advanced computational biophysics tools, such as Markov State Models and N-body Information Theory, has identified a lipid-regulated functional gate in fungal nhTMEM16 scramblase. We found how a sequence of lipid-triggered reorganizations of interactions between the residues of this gate and the permeating lipids can allow the groove to open and translocate lipids. Furthermore, we predicted how the analogous gate in mammalian mTMEM16F can be allosterically modulated by destabilization of the Ca2+ ion bound at the unique distal site to transform the groove in this homologue into an open, lipid scrambling competent state. Taken together, our studies suggest that TMEM16 scramblases utilize a common open-groove mechanism for lipid translocation.

Bio:

Dr. George Khelashvili received bachelor’s and master’s degrees in physics at Tbilisi State University, in Tbilisi, Georgia. His graduate studies at Illinois Institute of Technology in Chicago, under the mentorship of Prof. Larry Scott, were in the field of computational biophysics of lipid membranes. After receiving PhD in 2005, he continued his research training as a postdoctoral associate in Prof. Harel Weinstein’s lab at the Department of Physiology and Biophysics at Weill Cornell Medical College in New York City. During his postdoctoral studies, George became fascinated by understanding of the mechanistic role lipid membranes play in function and organization of membrane-associated proteins, as he immersed into exploration of protein-lipid interactions with advanced computational biophysics approaches. His interest in this topic only deepened with time and currently, as an Assistant Professor at Weill Cornell, George is pursuing studies of functional mechanisms of various physiologically important membrane-associated molecular systems, such as transporters, G protein-coupled receptors, lipid scramblases and ion channels.

If you are unable to attend in person, please join the Zoom Meeting here:
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