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Wright SC, Cañizal MCA, Benkel T, Simon K, Le Gouill C, Matricon P, Namkung Y, Lukasheva V, König GM, Laporte SA, Carlsson J, Kostenis E, Bouvier M, Schulte G, Hoffmann C
Sci Signal 11 (559) eaar5536 [2018-12-04; online 2018-12-04]
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.
PubMed 30514810
DOI 10.1126/scisignal.aar5536
Crossref 10.1126/scisignal.aar5536
pii: 11/559/eaar5536