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dc.contributor.authorSchönegge, Anne-Marie
Gallion, Jonathan
Picard, Louis-Philippe
Wilkins, Angela D.
Gouill, Christian Le
Audet, Martin
Stallaert, Wayne
Lohse, Martin J.
Kimmel, Marek
Lichtarge, Olivier
Bouvier, Michel
dc.date.accessioned 2019-01-09T17:21:15Z
dc.date.available 2019-01-09T17:21:15Z
dc.date.issued 2017
dc.identifier.citation Schönegge, Anne-Marie, Gallion, Jonathan, Picard, Louis-Philippe, et al.. "Evolutionary action and structural basis of the allosteric switch controlling β2AR functional selectivity." Nature Communications, 8, (2017) Springer Nature: https://doi.org/10.1038/s41467-017-02257-x.
dc.identifier.urihttps://hdl.handle.net/1911/105030
dc.description.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.
dc.language.iso eng
dc.publisher Springer Nature
dc.rights This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.title Evolutionary action and structural basis of the allosteric switch controlling β2AR functional selectivity
dc.type Journal article
dc.citation.journalTitle Nature Communications
dc.citation.volumeNumber 8
dc.identifier.digital s41467-017-02257-x
dc.type.dcmi Text
dc.identifier.doihttps://doi.org/10.1038/s41467-017-02257-x
dc.identifier.pmcid PMC5735088
dc.identifier.pmid 29255305
dc.type.publication publisher version
dc.citation.articleNumber 2169


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This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
Except where otherwise noted, this item's license is described as This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.