Computationally designed GPCR quaternary structures bias signaling pathway activation

Justine S. Paradis, Xiang Feng, Brigitte Murat, Robert E. Jefferson, Badr Sokrat, Martyna Szpakowska, Mireille Hogue, Nick D. Bergkamp, Franziska M. Heydenreich, Martine J. Smit, Andy Chevigné, Michel Bouvier () and Patrick Barth ()
Additional contact information
Justine S. Paradis: Université de Montréal
Xiang Feng: Ecole Polytechnique Fédérale de Lausanne
Brigitte Murat: Université de Montréal
Robert E. Jefferson: Ecole Polytechnique Fédérale de Lausanne
Badr Sokrat: Université de Montréal
Martyna Szpakowska: Luxembourg Institute of Health
Mireille Hogue: Université de Montréal
Nick D. Bergkamp: Vrije Universiteit
Franziska M. Heydenreich: Université de Montréal
Martine J. Smit: Vrije Universiteit
Andy Chevigné: Luxembourg Institute of Health
Michel Bouvier: Université de Montréal
Patrick Barth: Ecole Polytechnique Fédérale de Lausanne

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Communication across membranes controls critical cellular processes and is achieved by receptors translating extracellular signals into selective cytoplasmic responses. While receptor tertiary structures can be readily characterized, receptor associations into quaternary structures are challenging to study and their implications in signal transduction remain poorly understood. Here, we report a computational approach for predicting receptor self-associations, and designing receptor oligomers with various quaternary structures and signaling properties. Using this approach, we designed chemokine receptor CXCR4 dimers with reprogrammed binding interactions, conformations, and abilities to activate distinct intracellular signaling proteins. In agreement with our predictions, the designed CXCR4s dimerized through distinct conformations and displayed different quaternary structural changes upon activation. Consistent with the active state models, all engineered CXCR4 oligomers activated the G protein Gi, but only specific dimer structures also recruited β-arrestins. Overall, we demonstrate that quaternary structures represent an important unforeseen mechanism of receptor biased signaling and reveal the existence of a bias switch at the dimer interface of several G protein-coupled receptors including CXCR4, mu-Opioid and type-2 Vasopressin receptors that selectively control the activation of G proteins vs β-arrestin-mediated pathways. The approach should prove useful for predicting and designing receptor associations to uncover and reprogram selective cellular signaling functions.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34382-7

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DOI: 10.1038/s41467-022-34382-7

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