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Agonist-induced dimer dissociation as a macromolecular step in G protein-coupled receptor signaling

Julian Petersen, Shane C. Wright, David Rodríguez, Pierre Matricon, Noa Lahav, Aviv Vromen, Assaf Friedler, Johan Strömqvist, Stefan Wennmalm, Jens Carlsson and Gunnar Schulte ()
Additional contact information
Julian Petersen: Karolinska Institutet
Shane C. Wright: Karolinska Institutet
David Rodríguez: Stockholm University
Pierre Matricon: Uppsala University
Noa Lahav: Institute of Chemistry, The Hebrew University of Jerusalem
Aviv Vromen: Institute of Chemistry, The Hebrew University of Jerusalem
Assaf Friedler: Institute of Chemistry, The Hebrew University of Jerusalem
Johan Strömqvist: Single Technologies AB
Stefan Wennmalm: Royal Institute of Technology
Jens Carlsson: Uppsala University
Gunnar Schulte: Karolinska Institutet

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract G protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors. They can exist and act as dimers, but the requirement of dimers for agonist-induced signal initiation and structural dynamics remains largely unknown. Frizzled 6 (FZD6) is a member of Class F GPCRs, which bind WNT proteins to initiate signaling. Here, we show that FZD6 dimerizes and that the dimer interface of FZD6 is formed by the transmembrane α-helices four and five. Most importantly, we present the agonist-induced dissociation/re-association of a GPCR dimer through the use of live cell imaging techniques. Further analysis of a dimerization-impaired FZD6 mutant indicates that dimer dissociation is an integral part of FZD6 signaling to extracellular signal-regulated kinases1/2. The discovery of agonist-dependent dynamics of dimers as an intrinsic process of receptor activation extends our understanding of Class F and other dimerizing GPCRs, offering novel targets for dimer-interfering small molecules.

Date: 2017
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DOI: 10.1038/s41467-017-00253-9

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