Dynamic Cholesterol-Conditioned Dimerization of the G Protein Coupled Chemokine Receptor Type 4

PLoS Comput Biol. 2016 Nov 3;12(11):e1005169. doi: 10.1371/journal.pcbi.1005169. eCollection 2016 Nov.

Abstract

G protein coupled receptors (GPCRs) allow for the transmission of signals across biological membranes. For a number of GPCRs, this signaling was shown to be coupled to prior dimerization of the receptor. The chemokine receptor type 4 (CXCR4) was reported before to form dimers and their functionality was shown to depend on membrane cholesterol. Here, we address the dimerization pattern of CXCR4 in pure phospholipid bilayers and in cholesterol-rich membranes. Using ensembles of molecular dynamics simulations, we show that CXCR4 dimerizes promiscuously in phospholipid membranes. Addition of cholesterol dramatically affects the dimerization pattern: cholesterol binding largely abolishes the preferred dimer motif observed for pure phospholipid bilayers formed mainly by transmembrane helices 1 and 7 (TM1/TM5-7) at the dimer interface. In turn, the symmetric TM3,4/TM3,4 interface is enabled first by intercalating cholesterol molecules. These data provide a molecular basis for the modulation of GPCR activity by its lipid environment.

MeSH terms

  • Binding Sites
  • Cholesterol / chemistry*
  • Computer Simulation
  • Kinetics
  • Lipid Bilayers / chemistry*
  • Models, Chemical*
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Conformation
  • Protein Multimerization*
  • Receptors, CXCR4 / chemistry*
  • Receptors, CXCR4 / ultrastructure*
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / ultrastructure
  • Structure-Activity Relationship

Substances

  • CXCR4 protein, human
  • Lipid Bilayers
  • Receptors, CXCR4
  • Receptors, G-Protein-Coupled
  • Cholesterol

Grants and funding

This work was supported by DFG RTG 1962/1 www.dfg.de. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.