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- Title
FZD<sub>5</sub> is a Gαq-coupled receptor that exhibits the functional hallmarks of prototypical GPCRs.
- Authors
Wright, Shane C.; Cañizal, Maria Consuelo Alonso; Benkel, Tobias; Simon, Katharina; Le Gouill, Christian; Matricon, Pierre; Namkung, Yoon; Lukasheva, Viktoria; König, Gabriele M.; Laporte, Stéphane A.; Carlsson, Jens; Kostenis, Evi; Bouvier, Michel; Schulte, Gunnar; Hoffmann, Carsten
- Abstract
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.
- Subjects
MEMBRANE proteins; G protein coupled receptors; CELL receptors; STEM cells; CATENIN genetics
- Publication
Science Signaling, 2018, Vol 11, Issue 559, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.aar5536