1). Mechanisms of lipid scrambling by GPCR and TMEM16 proteins
2). Structural basis of ω-3 fatty acid transport across the blood-brain barrier
3). Mechanistic underlying receptor-mediated cellular vitamin A uptake
My lab explores molecular-level structural and dynamic mechanisms underlying function of various membrane protein systems (e.g., G protein-coupled receptors, transporters, ion channels, lipid scramblases) using advanced computational biophysics and machine learning approaches.
The overall goal of the research projects in the lab is to uncover dynamic mechanisms in fundamental biological processes of signal transduction by cell surface proteins in the categories of receptors (such as G protein-coupled receptors, GPCRs), transporters in the family of Neurotransmitter:Sodium-Symporters (NSS), and lipid scramblases.
Special emphasis is on understanding how the spatial organization and function of these molecular machines are regulated by the cell membrane, its components (i.e. cholesterol, various lipids), and interactions with the rich environment of the cell’s proteins. We approach these research topics with advanced quantitative methods of theoretical and computational biophysics, developed and utilized at the highest level of each specialty. We pursue interdisciplinary and multi-scale strategies that integrate biophysical theory and computation with biophysical measurements and molecular cell biology experimentation.
Our approach takes advantage of an abundance of molecular level insights from experimental explorations of the function and interactions of membrane-associated signaling proteins, and interprets them in a novel quantitative multi-scale framework to yield insights based on energetics, and experimentally testable hypotheses we validate with respect to mechanisms by which membrane properties and remodeling (e.g. curvature, lipid segregation) affect protein function, organization and signaling-associated interactions that are of major importance to cell physiology.
Figure 1
Biography
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 Medicine. Currently, as an Assistant Professor at the Department of Physiology and Biophysics, 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.
Distinctions:
My PhD thesis titled “Theoretical and Simulation Study of Lipid Membranes: Application to Lipid Rafts” was published as a textbook monograph
As a developer of a new computational technique for mesoscale modelling of protein-membrane interactions based on continuum mean-field theory I was invited to contribute a book chapter in “Methods in Molecular Biology”. In this book series, authors are asked to describe detailed protocol of their novel technique so that other peers in the field can use the method. https://link.springer.com/protocol/10.1007/978-1-4939-8760-3_2
Recognized for influential work in the field, I was invited number of times to write a review chapter for various journals, the most recently (in 2022) for Annual Reviews in Biophysics.
Selected Publications:
Bergman S, Cater R, Plante A, Mancia F, Khelashvili G – Substrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A. Nature Communications 2023, 14(1):3391. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10250862/
Khelashvili G, Kots E, Cheng X, Levine M, Weinstein H – The allosteric mechanism leading to an open-groove lipid conductive state of the TMEM16F scramblase. Nature Communications Biology 2022, 5(1):990. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9484709/
Morra G, Razavi A, Menon AK, Khelashvili G – Cholesterol populates the lipid translocation pathway to block phospholipid scrambling by a G protein-coupled receptor. Structure 2022, 30(8):1208-1217. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9356978/
Cater R, Chua G-L, Erramilli S, Keener J, Choy B, Tokarz P, Chin C, Quek D, Kloss B, Pepe J, Parisi G, Wong B, Clarke O, Marty M, Kossiakoff A, Khelashvili G, Silver D, Mancia F – Structural basis of MFSD2A-mediated ω-3 fatty acid transport. Nature 2021, 595(7866):315-319. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266758/
Khelashvili G, Chauhan N, Pandey K, Eliezer D, Menon AK – Exchange of water for sterol underlies sterol egress from a StARkin domain. eLife 2019, 8. pii: e53444. https://pubmed.ncbi.nlm.nih.gov/31799930/
