Evolutionary action and structural basis of the allosteric switch controlling β2AR functional selectivity

Anne-Marie Schönegge, Jonathan Gallion, Louis-Philippe Picard, Angela D. Wilkins, Christian Gouill, Martin Audet, Wayne Stallaert, Martin J. Lohse, Marek Kimmel, Olivier Lichtarge and Michel Bouvier ()
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Anne-Marie Schönegge: Université de Montreal
Jonathan Gallion: Baylor College of Medicine
Louis-Philippe Picard: Université de Montreal
Angela D. Wilkins: Baylor College of Medicine
Christian Gouill: Université de Montreal
Martin Audet: Université de Montreal
Wayne Stallaert: Université de Montreal
Martin J. Lohse: Institute of Pharmacology and Toxicology
Marek Kimmel: Rice University
Olivier Lichtarge: Baylor College of Medicine
Michel Bouvier: Université de Montreal

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

Abstract: Abstract Functional selectivity of G-protein-coupled receptors is believed to originate from ligand-specific conformations that activate only subsets of signaling effectors. In this study, to identify molecular motifs playing important roles in transducing ligand binding into distinct signaling responses, we combined in silico evolutionary lineage analysis and structure-guided site-directed mutagenesis with large-scale functional signaling characterization and non-negative matrix factorization clustering of signaling profiles. Clustering based on the signaling profiles of 28 variants of the β2-adrenergic receptor reveals three clearly distinct phenotypical clusters, showing selective impairments of either the Gi or βarrestin/endocytosis pathways with no effect on Gs activation. Robustness of the results is confirmed using simulation-based error propagation. The structural changes resulting from functionally biasing mutations centered around the DRY, NPxxY, and PIF motifs, selectively linking these micro-switches to unique signaling profiles. Our data identify different receptor regions that are important for the stabilization of distinct conformations underlying functional selectivity.

Date: 2017
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DOI: 10.1038/s41467-017-02257-x

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