Mechanisms of Lipid Scrambling by the G Protein-Coupled Receptor Opsin

Morra, Giulia; Razavi, Asghar M.; Pandey, Kalpana; Weinstein, Harel; Menon, Anant K.; Khelashvili, George

doi:10.1016/j.str.2017.11.020

Title: Mechanisms of Lipid Scrambling by the G Protein-Coupled Receptor Opsin

Journal Article · Thu Dec 28 00:00:00 EST 2017 · Structure

DOI:https://doi.org/10.1016/j.str.2017.11.020· OSTI ID:1548857

Morra, Giulia; Razavi, Asghar M.; Pandey, Kalpana; Weinstein, Harel; Menon, Anant K.; Khelashvili, George

Several class-A G protein-coupled receptor (GPCR) proteins act as constitutive phospholipid scramblases catalyzing the transbilayer translocation of >10,000 phospholipids per second when reconstituted into synthetic vesicles. To address the molecular mechanism by which these proteins facilitate rapid lipid scrambling, we carried out large-scale ensemble atomistic molecular dynamics simulations of the opsin GPCR. We report here that, in the process of scrambling, lipid head groups traverse a dynamically revealed hydrophilic pathway in the region between transmembrane helices 6 and 7 of the protein while their hydrophobic tails remain in the bilayer environment. We present quantitative kinetic models of the translocation process based on Markov State Model analysis. As key residues on the lipid translocation pathway are conserved within the class-A GPCR family, our results illuminate unique aspects of GPCR structure and dynamics while providing a rigorous basis for the design of variants of these proteins with defined scramblase activity.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH); Velux Stiftung

Grant/Contract Number:: AC05-00OR22725; AC02-05CH11231; EY028314; EY024207

OSTI ID:: 1548857

Alternate ID(s):: OSTI ID: 1479002

Journal Information:: Structure, Journal Name: Structure Vol. 26 Journal Issue: 2; ISSN 0969-2126

Publisher:: ElsevierCopyright Statement

Country of Publication:: United Kingdom

Language:: English

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Cited by: 36 works

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Title: Mechanisms of Lipid Scrambling by the G Protein-Coupled Receptor Opsin

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