Journal
STRUCTURE
Volume 26, Issue 2, Pages 356-+Publisher
CELL PRESS
DOI: 10.1016/j.str.2017.11.020
Keywords
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Funding
- NIH [EY028314, EY024207]
- Velux Stiftung [881]
- HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute of Computational Biomedicine at Weill Cornell Medical College
- Office of Science of the U.S. Department of Energy [BIP109, DE-AC05-00OR22725]
- Office of Science of the US Department of Energy [DE-AC02-05CH11231, m1710]
- NATIONAL EYE INSTITUTE [R21EY024207, R21EY028314] Funding Source: NIH RePORTER
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Several class-A G protein-coupled receptor (GPCR) proteins act as constitutive phospholipid scram-blases 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 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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