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Structure. 2018 Feb 6;26(2):356-367.e3. doi: 10.1016/j.str.2017.11.020. Epub 2017 Dec 28.

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

Author information

1
Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, Room LC-501A, New York, NY 10065, USA; Istituto di Chimica del Riconoscimento Molecolare, CNR, Via Mario Bianco 9, 20131 Milan, Italy.
2
Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, Room LC-501A, New York, NY 10065, USA.
3
Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
4
Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, Room LC-501A, New York, NY 10065, USA; Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065, USA.
5
Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, Room LC-501A, New York, NY 10065, USA; Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: gek2009@med.cornell.edu.

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 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.

KEYWORDS:

GPCR; Markov state models; adaptive sampling; lipid flip-flop; molecular dynamics simulations; phospholipid; rhodopsin; scramblase

PMID:
29290486
PMCID:
PMC5803311
[Available on 2019-02-06]
DOI:
10.1016/j.str.2017.11.020
[Indexed for MEDLINE]

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