Membrane cholesterol access into a G-protein-coupled receptor

Ramon Guixà-González, José L. Albasanz, Ismael Rodriguez-Espigares, Manuel Pastor, Ferran Sanz, Maria Martí-Solano, Moutusi Manna, Hector Martinez-Seara, Peter W. Hildebrand, Mairena Martín () and Jana Selent ()
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Ramon Guixà-González: Research Programme on Biomedical Informatics (GRIB)
José L. Albasanz: Organic Chemistry, and Biochemistry, Faculty of Science and Chemical Technologies and Faculty of Medicine of Ciudad Real. Regional Center of Biomedical Research (CRIB), University of Castilla-La Mancha (UCLM)
Ismael Rodriguez-Espigares: Research Programme on Biomedical Informatics (GRIB)
Manuel Pastor: Research Programme on Biomedical Informatics (GRIB)
Ferran Sanz: Research Programme on Biomedical Informatics (GRIB)
Maria Martí-Solano: Research Programme on Biomedical Informatics (GRIB)
Moutusi Manna: Tampere University of Technology (TUT)
Hector Martinez-Seara: Tampere University of Technology (TUT)
Peter W. Hildebrand: Institut für Medizinische Physik und Biophysik, AG ProteiInformatics, Charité-Universitätsmedizin Berlin
Mairena Martín: Organic Chemistry, and Biochemistry, Faculty of Science and Chemical Technologies and Faculty of Medicine of Ciudad Real. Regional Center of Biomedical Research (CRIB), University of Castilla-La Mancha (UCLM)
Jana Selent: Research Programme on Biomedical Informatics (GRIB)

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Cholesterol is a key component of cell membranes with a proven modulatory role on the function and ligand-binding properties of G-protein-coupled receptors (GPCRs). Crystal structures of prototypical GPCRs such as the adenosine A2A receptor (A2AR) have confirmed that cholesterol finds stable binding sites at the receptor surface suggesting an allosteric role of this lipid. Here we combine experimental and computational approaches to show that cholesterol can spontaneously enter the A2AR-binding pocket from the membrane milieu using the same portal gate previously suggested for opsin ligands. We confirm the presence of cholesterol inside the receptor by chemical modification of the A2AR interior in a biotinylation assay. Overall, we show that cholesterol’s impact on A2AR-binding affinity goes beyond pure allosteric modulation and unveils a new interaction mode between cholesterol and the A2AR that could potentially apply to other GPCRs.

Date: 2017
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DOI: 10.1038/ncomms14505

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