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 ()
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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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