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

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.Frizzled 6 (FZD₆) is a G protein-coupled receptor (GPCR) involved in several cellular processes. Here, the authors use live cell imaging and spectroscopy to show that FZD₆ forms dimers, whose association is regulated by WNT proteins and that dimer dissociation is crucial for FZD₆ signaling.