Anionic phospholipids control mechanisms of GPCR-G protein recognition

Naveen Thakur, Arka P. Ray, Liam Sharp, Beining Jin, Alexander Duong, Niloofar Gopal Pour, Samuel Obeng, Anuradha V. Wijesekara, Zhan-Guo Gao, Christopher R. McCurdy, Kenneth A. Jacobson, Edward Lyman and Matthew T. Eddy ()
Additional contact information
Naveen Thakur: University of Florida
Arka P. Ray: University of Florida
Liam Sharp: University of Delaware
Beining Jin: University of Florida
Alexander Duong: University of Florida
Niloofar Gopal Pour: University of Florida
Samuel Obeng: University of Florida
Anuradha V. Wijesekara: University of Florida
Zhan-Guo Gao: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Christopher R. McCurdy: University of Florida
Kenneth A. Jacobson: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Edward Lyman: University of Delaware
Matthew T. Eddy: University of Florida

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract G protein-coupled receptors (GPCRs) are embedded in phospholipids that strongly influence drug-stimulated signaling. Anionic lipids are particularly important for GPCR signaling complex formation, but a mechanism for this role is not understood. Using NMR spectroscopy, we explore the impact of anionic lipids on the function-related conformational equilibria of the human A2A adenosine receptor (A2AAR) in bilayers containing defined mixtures of zwitterionic and anionic phospholipids. Anionic lipids prime the receptor to form complexes with G proteins through a conformational selection process. Without anionic lipids, signaling complex formation proceeds through a less favorable induced fit mechanism. In computational models, anionic lipids mimic interactions between a G protein and positively charged residues in A2AAR at the receptor intracellular surface, stabilizing a pre-activated receptor conformation. Replacing these residues strikingly alters the receptor response to anionic lipids in experiments. High sequence conservation of the same residues among all GPCRs supports a general role for lipid-receptor charge complementarity in signaling.

Date: 2023
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DOI: 10.1038/s41467-023-36425-z

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