Mechanisms of Lipid Scrambling by the G Protein-Coupled Receptor Opsin
Abstract
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.
- Authors:
- Publication Date:
- Research Org.:
- 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 Org.:
- USDOE Office of Science (SC); National Institutes of Health (NIH); Velux Stiftung
- OSTI Identifier:
- 1548857
- Alternate Identifier(s):
- OSTI ID: 1479002
- Grant/Contract Number:
- AC05-00OR22725; AC02-05CH11231; EY028314; EY024207
- Resource Type:
- Published Article
- Journal Name:
- Structure
- Additional Journal Information:
- Journal Name: Structure Journal Volume: 26 Journal Issue: 2; Journal ID: ISSN 0969-2126
- Publisher:
- Elsevier
- Country of Publication:
- United Kingdom
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; lipid flip-flop; scramblase; adaptive sampling; Markov state models; molecular dynamics simulations; GPCR; phospholipid; rhodopsin
Citation Formats
Morra, Giulia, Razavi, Asghar M., Pandey, Kalpana, Weinstein, Harel, Menon, Anant K., and Khelashvili, George. Mechanisms of Lipid Scrambling by the G Protein-Coupled Receptor Opsin. United Kingdom: N. p., 2017.
Web. doi:10.1016/j.str.2017.11.020.
Morra, Giulia, Razavi, Asghar M., Pandey, Kalpana, Weinstein, Harel, Menon, Anant K., & Khelashvili, George. Mechanisms of Lipid Scrambling by the G Protein-Coupled Receptor Opsin. United Kingdom. https://doi.org/10.1016/j.str.2017.11.020
Morra, Giulia, Razavi, Asghar M., Pandey, Kalpana, Weinstein, Harel, Menon, Anant K., and Khelashvili, George. Thu .
"Mechanisms of Lipid Scrambling by the G Protein-Coupled Receptor Opsin". United Kingdom. https://doi.org/10.1016/j.str.2017.11.020.
@article{osti_1548857,
title = {Mechanisms of Lipid Scrambling by the G Protein-Coupled Receptor Opsin},
author = {Morra, Giulia and Razavi, Asghar M. and Pandey, Kalpana and Weinstein, Harel and Menon, Anant K. and Khelashvili, George},
abstractNote = {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.},
doi = {10.1016/j.str.2017.11.020},
journal = {Structure},
number = 2,
volume = 26,
place = {United Kingdom},
year = {Thu Dec 28 00:00:00 EST 2017},
month = {Thu Dec 28 00:00:00 EST 2017}
}
https://doi.org/10.1016/j.str.2017.11.020
Web of Science
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