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.
Highlights
Gprotein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors
Depending on the specific GPCR class, dimers vary in their receptor complex formation, signaling, trafficking and pharmacology[32, 33]
It was shown that FZD1, FZD2, FZD3 dimerize and that dimerization of FZD3 and FZD7 affects WNT/β-catenin signaling in Xenopus laevis[14, 15]
Summary
Gprotein-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. 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. Based on live cell imaging experiments, we provide evidence that FZD6 dimerizes and that the dimer undergoes WNT-5Ainduced dissociation and re-association. Our results suggest that the FZD6 monomer, and not the dimer, is the minimal signaling unit supporting the idea that receptor dissociation precedes signal initiation
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