Modulation of adenosine A2a receptor oligomerization by receptor activation and PIP2 interactions
- PMID: 34270937
- PMCID: PMC8581623
- DOI: 10.1016/j.str.2021.06.015
Modulation of adenosine A2a receptor oligomerization by receptor activation and PIP2 interactions
Abstract
GPCRs have been shown to form oligomers, which generate distinctive signaling outcomes. However, the structural nature of the oligomerization process remains uncertain. We have characterized oligomeric configurations of the adenosine A2a receptor (A2aR) by combining large-scale molecular dynamics simulations with Markov state models. These oligomeric structures may also serve as templates for studying oligomerization of other class A GPCRs. Our simulation data revealed that receptor activation results in enhanced oligomerization, more diverse oligomer populations, and a more connected oligomerization network. The active state conformation of the A2aR shifts protein-protein association interfaces to those involving intracellular loop ICL3 and transmembrane helix TM6. Binding of PIP2 to A2aR stabilizes protein-protein interactions via PIP2-mediated association interfaces. These results indicate that A2aR oligomerization is responsive to the local membrane lipid environment. This, in turn, suggests a modulatory effect on A2aR whereby a given oligomerization profile favors the dynamic formation of specific supramolecular signaling complexes.
Keywords: A2a receptor; GPCR; Markov state models; lipids; molecular dynamics; oligomerization.
Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.
Conflict of interest statement
Declaration of interests The authors declare no competing interests. M.S.P.S. is on the journal advisory board.
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