Evolutionary action and structural basis of the allosteric switch controlling β\(_2\)AR functional selectivity

Please always quote using this URN: urn:nbn:de:bvb:20-opus-172268
  • 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 theFunctional 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.show moreshow less

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Metadaten
Author: Anne-Marie Schönegge, Jonathan Gallion, Louis-Philippe Picard, Angela D. Wilkins, Christian Le Gouill, Martin Audet, Wayne Stallaert, Martin J. Lohse, Marek Kimmel, Olivier Lichtarge, Michel Bouvier
URN:urn:nbn:de:bvb:20-opus-172268
Document Type:Journal article
Faculties:Medizinische Fakultät / Institut für Pharmakologie und Toxikologie
Language:English
Parent Title (English):Nature Communications
Year of Completion:2017
Volume:8
Article Number:2169
Source:Nature Communications (2017) 8:2169. https://doi.org/10.1038/s41467-017-02257-x
DOI:https://doi.org/10.1038/s41467-017-02257-x
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=29255305
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:functional clustering; molecular modelling; protein design; receptor pharmacology; toxicology
Release Date:2021/02/19
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International