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Evolutionary action and structural basis of the allosteric switch controlling β(2)AR functional selectivity

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Item Type:Article
Title:Evolutionary action and structural basis of the allosteric switch controlling β(2)AR functional selectivity
Creators Name:Schönegge, A.M. and Gallion, J. and Picard, L.P. and Wilkins, A.D. and Le Gouill, C. and Audet, M. and Stallaert, W. and Lohse, M.J. and Kimmel, M. and Lichtarge, O. and Bouvier, M.
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 β(2)-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.
Keywords:Adrenergic beta-Agonists, Base Sequence, beta-2 Adrenergic Receptors, Cluster Analysis, GTP-Binding Proteins, HEK293 Cells, Isoproterenol, Molecular Evolution, Molecular Models, Mutation, Protein Binding, Protein Domains, Signal Transduction
Source:Nature Communications
ISSN:2041-1723
Publisher:Nature Publishing Group (U.K.)
Volume:8
Number:1
Page Range:2169
Date:18 December 2017
Official Publication:https://doi.org/10.1038/s41467-017-02257-x
PubMed:View item in PubMed

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