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, Gunnar Schulte

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 (FZD 4,5,6,7, 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.

Original languageEnglish (US)
Article number667
JournalNature Communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

Drug Receptors
Metagenomics
Basic Amino Acids
Phosphoproteins
Energy Transfer
Molecular Dynamics Simulation
Drug Delivery Systems
GTP-Binding Proteins
Mutagenesis
switches
Chemical activation
Switches
activation
Mutation
Neoplasms
Energy transfer
Conformations
Molecular dynamics
Assays
Therapeutics

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Wright, S. C., Kozielewicz, P., Kowalski-Jahn, M., Petersen, J., Bowin, C. F., Slodkowicz, G., ... Schulte, G. (2019). A conserved molecular switch in Class F receptors regulates receptor activation and pathway selection. Nature Communications, 10(1), [667]. https://doi.org/10.1038/s41467-019-08630-2

A conserved molecular switch in Class F receptors regulates receptor activation and pathway selection. / Wright, Shane C.; Kozielewicz, Paweł; Kowalski-Jahn, Maria; Petersen, Julian; Bowin, Carl Fredrik; Slodkowicz, Greg; Marti-Solano, Maria; Rodríguez, David; Hot, Belma; Okashah, Najeah; Strakova, Katerina; Valnohova, Jana; Babu, M. Madan; Lambert, Nevin A.; Carlsson, Jens; Schulte, Gunnar.

In: Nature Communications, Vol. 10, No. 1, 667, 01.12.2019.

Research output: Contribution to journalArticle

Wright, SC, Kozielewicz, P, Kowalski-Jahn, M, Petersen, J, Bowin, CF, Slodkowicz, G, Marti-Solano, M, Rodríguez, D, Hot, B, Okashah, N, Strakova, K, Valnohova, J, Babu, MM, Lambert, NA, Carlsson, J & Schulte, G 2019, 'A conserved molecular switch in Class F receptors regulates receptor activation and pathway selection', Nature Communications, vol. 10, no. 1, 667. https://doi.org/10.1038/s41467-019-08630-2
Wright SC, Kozielewicz P, Kowalski-Jahn M, Petersen J, Bowin CF, Slodkowicz G et al. A conserved molecular switch in Class F receptors regulates receptor activation and pathway selection. Nature Communications. 2019 Dec 1;10(1). 667. https://doi.org/10.1038/s41467-019-08630-2
Wright, Shane C. ; Kozielewicz, Paweł ; Kowalski-Jahn, Maria ; Petersen, Julian ; Bowin, Carl Fredrik ; Slodkowicz, Greg ; Marti-Solano, Maria ; Rodríguez, David ; Hot, Belma ; Okashah, Najeah ; Strakova, Katerina ; Valnohova, Jana ; Babu, M. Madan ; Lambert, Nevin A. ; Carlsson, Jens ; Schulte, Gunnar. / A conserved molecular switch in Class F receptors regulates receptor activation and pathway selection. In: Nature Communications. 2019 ; Vol. 10, No. 1.
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