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Membrane cholesterol access into a G-protein-coupled receptor

Author

Listed:
  • Ramon Guixà-González

    (Research Programme on Biomedical Informatics (GRIB)
    Institut für Medizinische Physik und Biophysik, AG ProteiInformatics, Charité-Universitätsmedizin Berlin)

  • 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)
    Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic)

  • 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))

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.

Suggested Citation

  • 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 &, 2017. "Membrane cholesterol access into a G-protein-coupled receptor," Nature Communications, Nature, vol. 8(1), pages 1-12, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14505
    DOI: 10.1038/ncomms14505
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    Cited by:

    1. Talia Zeppelin & Lucy Kate Ladefoged & Steffen Sinning & Xavier Periole & Birgit Schiøtt, 2018. "A direct interaction of cholesterol with the dopamine transporter prevents its out-to-inward transition," PLOS Computational Biology, Public Library of Science, vol. 14(1), pages 1-24, January.

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