A conserved molecular switch in Class F receptors regulates receptor activation and pathway selection

Shane C. Wright, Paweł Kozielewicz, Maria Kowalski-Jahn, Julian Petersen, Carl-Fredrik Bowin, Greg Slodkowicz, Maria Marti-Solano, David Rodríguez, Belma Hot, Najeah Okashah, Katerina Strakova, Jana Valnohova, M. Madan Babu, Nevin A. Lambert, Jens Carlsson and Gunnar Schulte ()
Additional contact information
Shane C. Wright: Karolinska Institutet
Paweł Kozielewicz: Karolinska Institutet
Maria Kowalski-Jahn: Karolinska Institutet
Julian Petersen: Karolinska Institutet
Carl-Fredrik Bowin: Karolinska Institutet
Greg Slodkowicz: MRC Laboratory of Molecular Biology
Maria Marti-Solano: MRC Laboratory of Molecular Biology
David Rodríguez: Uppsala University
Belma Hot: Karolinska Institutet
Najeah Okashah: Medical College of Georgia at Augusta University
Katerina Strakova: Karolinska Institutet
Jana Valnohova: Karolinska Institutet
M. Madan Babu: MRC Laboratory of Molecular Biology
Nevin A. Lambert: Medical College of Georgia at Augusta University
Jens Carlsson: Uppsala University
Gunnar Schulte: Karolinska Institutet

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract Class F receptors are considered valuable therapeutic targets due to their role in human disease, but structural changes accompanying receptor activation remain unexplored. Employing population and cancer genomics data, structural analyses, molecular dynamics simulations, resonance energy transfer-based approaches and mutagenesis, we identify a conserved basic amino acid in TM6 in Class F receptors that acts as a molecular switch to mediate receptor activation. Across all tested Class F receptors (FZD4,5,6,7, SMO), mutation of the molecular switch confers an increased potency of agonists by stabilizing an active conformation as assessed by engineered mini G proteins as conformational sensors. Disruption of the switch abrogates the functional interaction between FZDs and the phosphoprotein Dishevelled, supporting conformational selection as a prerequisite for functional selectivity. Our studies reveal the molecular basis of a common activation mechanism conserved in all Class F receptors, which facilitates assay development and future discovery of Class F receptor-targeting drugs.

Date: 2019
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08630-2

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DOI: 10.1038/s41467-019-08630-2

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