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- Title
Anionic phospholipids control mechanisms of GPCR-G protein recognition.
- Authors
Thakur, Naveen; Ray, Arka P.; Sharp, Liam; Jin, Beining; Duong, Alexander; Pour, Niloofar Gopal; Obeng, Samuel; Wijesekara, Anuradha V.; Gao, Zhan-Guo; McCurdy, Christopher R.; Jacobson, Kenneth A.; Lyman, Edward; Eddy, Matthew T.
- 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. In cell membranes, lipids are ubiquitous regulators of protein function. Here, Thakur et al. observe anionic phospholipids impact the conformational dynamics of a class A human GPCR.
- Subjects
G protein coupled receptors; PHOSPHOLIPIDS; G proteins; NUCLEAR magnetic resonance spectroscopy; PROTEINS; CELL membranes
- Publication
Nature Communications, 2023, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-36425-z