FZD5 is a Gαq-coupled receptor that exhibits the functional hallmarks of prototypical GPCRs

• Published in: Science signaling 2018-12, Vol.11 (559)
• Main Authors: Wright, Shane C, Cañizal Maria Consuelo Alonso, Benkel Tobias, Simon, Katharina, Le Gouill Christian, Matricon Pierre, Yoon, Namkung, Lukasheva Viktoria, König, Gabriele M, Laporte, Stéphane A, Carlsson Jens, Kostenis Evi, Bouvier, Michel, Schulte, Gunnar, Hoffmann, Carsten
• Format: Article
• Language: English
• Subjects: Activation; Binding; Cascades; Cellular manufacture; Deactivation; Drug discovery; Embryogenesis; Embryonic growth stage; Energy transfer; Fluorescence; Fluorescence recovery after photobleaching; Frizzled protein; G protein-coupled receptors; Homeostasis; Inactivation; Kinases; Ligands; Medicin och hälsovetenskap; Photobleaching; Proteins; Receptors; Second messengers; Signaling; Spectrometry; Stem cells; Wnt protein; β-catenin
• ISSN: 1945-0877; 1937-9145; 1937-9145
• DOI: 10.1126/scisignal.aar5536

FZD5 as a prototypical GPCRDespite exhibiting sequence and structural similarity to other classes of G protein–coupled receptors (GPCRs), class F family members are generally not considered to be prototypical GPCRs. Wright et al. found that the class F GPCR FZD5 exhibited many of the functional characteristics of GPCRs. FZD5 underwent a conformational change similar to that of conventional GPCRs upon ligand binding. Ligand binding also caused FZD5 to activate signaling through Gαq-containing heterotrimeric G proteins. FZD5-mediated activation of Gαq elicited the production of second messengers, the activation of kinases, and cellular responses typical of G protein activation by classical GPCRs. These findings suggest that FZD5 and other class F GPCRs may not differ from prototypical GPCRs as much as was previously thought.Frizzleds (FZDs) are a group of seven transmembrane–spanning (7TM) receptors that belong to class F of the G protein–coupled receptor (GPCR) superfamily. FZDs bind WNT proteins to stimulate diverse signaling cascades involved in embryonic development, stem cell regulation, and adult tissue homeostasis. Frizzled 5 (FZD5) is one of the most studied class F GPCRs that promote the functional inactivation of the β-catenin destruction complex in response to WNTs. However, whether FZDs function as prototypical GPCRs has been heavily debated and, in particular, FZD5 has not been shown to activate heterotrimeric G proteins. Here, we show that FZD5 exhibited a conformational change after the addition of WNT-5A, which is reminiscent of class A and class B GPCR activation. In addition, we performed several live-cell imaging and spectrometric-based approaches, such as dual-color fluorescence recovery after photobleaching (dcFRAP) and resonance energy transfer (RET)–based assays that demonstrated that FZD5 activated Gαq and its downstream effectors upon stimulation with WNT-5A. Together, these findings suggest that FZD5 is a 7TM receptor with a bona fide GPCR activation profile and suggest novel targets for drug discovery in WNT-FZD signaling.