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A conserved molecular switch in Class F receptors regulates receptor activation and pathway selection
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- Wright, SC (author)
- Karolinska Institutet,Karolinska Inst, Dept Physiol & Pharmacol, Sect Receptor Biol & Signaling, S-17165 Stockholm, Sweden
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- Kozielewicz, P (author)
- Karolinska Institutet,Karolinska Inst, Dept Physiol & Pharmacol, Sect Receptor Biol & Signaling, S-17165 Stockholm, Sweden
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- Kowalski-Jahn, M (author)
- Karolinska Institutet,Karolinska Inst, Dept Physiol & Pharmacol, Sect Receptor Biol & Signaling, S-17165 Stockholm, Sweden
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- (creator_code:org_t)
- 2019-02-08
- 2019
- English.
- In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 667-
- Journal article (peer-reviewed)
Abstract
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- 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.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
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- ref (subject category)
- art (subject category)
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- Wright, SC
- Kozielewicz, P
- Kowalski-Jahn, M
- Petersen, J
- Bowin, CF
- Slodkowicz, G
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- Marti-Solano, M
- Rodriguez, D
- Hot, B
- Okashah, N
- Strakova, K
- Valnohova, J
- Babu, MM
- Lambert, NA
- Carlsson, Jens
- Schulte, G
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- Karolinska Institutet
- Uppsala University
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