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

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Authors

PETERSEN J. WRIGHT SC RODRIGUEZ D. MATRICON P. LAHAV N. VROMEN A. FRIEDLER A. STROMQVIST J. WENNMALM S. CARLSSON J. SCHULTE Gunnar

Year of publication 2017
Type Article in Periodical
Magazine / Source Nature Communications
MU Faculty or unit

Faculty of Science

Citation
Doi http://dx.doi.org/10.1038/s41467-017-00253-9
Keywords CROSS-CORRELATION SPECTROSCOPY; MOLECULAR-DYNAMICS SIMULATIONS; A GPCR DIMERS; FRIZZLED 6; ADRENERGIC-RECEPTOR; CONSTANT-PRESSURE; COMPLEX; BINDING; OLIGOMERIZATION; DIMERIZATION
Description 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 a-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 agonistdependent dynamics of dimers as an intrinsic process of receptor activation extends our understanding of Class F and other dimerizing GPCRs, offering novel targets for dimerinterfering small molecules.
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