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

Kristyna Pluhackova, Stefan Gahbauer, Franziska Kranz, Tsjerk A. Wassenaar, Rainer A. Boeckmann*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

49 Citations (Scopus)
198 Downloads (Pure)

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.
Original languageEnglish
Article number1005169
Number of pages25
JournalPLoS Computational Biology
Volume12
Issue number11
DOIs
Publication statusPublished - Nov-2016

Keywords

  • COARSE-GRAINED MODEL
  • CRYSTAL-STRUCTURE
  • FORCE-FIELD
  • MOLECULAR-DYNAMICS
  • OPIOID RECEPTOR
  • BETA(2)-ADRENERGIC RECEPTOR
  • BIOMOLECULAR SIMULATIONS
  • HIV-1 CORECEPTOR
  • STRUCTURAL BASIS
  • BINDING-SITES

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