Dynamic Cholesterol-Conditioned Dimerization of the G Protein Coupled Chemokine Receptor Type 4.
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.
Computational Biology, Department of Biology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
Kristyna
K
Pluhackova
Computational Biology, Department of Biology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
Stefan
S
Gahbauer
Computational Biology, Department of Biology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.|Computer Graphics, Department of Computer Science, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
Franziska
F
Kranz
Computational Biology, Department of Biology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.|Groningen Biomolecular Sciences and Biotechnology and Zernike Institute of Advanced Materials, University of Groningen, The Netherlands.
Tsjerk A
http://orcid.org/0000-0002-6345-0266
TA
Wassenaar
Computational Biology, Department of Biology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
Rainer A
http://orcid.org/0000-0002-9325-5162
RA
Böckmann
D001665:Binding Sites; D002784:Cholesterol / Q000737:chemistry*; D003198:Computer Simulation; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry*; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D019718:Receptors, CXCR4 / Q000737:chemistry* / Q000648:ultrastructure*; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000648:ultrastructure; D013329:Structure-Activity Relationship
C527276:CXCR4 protein, human; D008051:Lipid Bilayers; D019718:Receptors, CXCR4; D043562:Receptors, G-Protein-Coupled; D002784:Cholesterol