FZD5 is a G{alpha}q-coupled receptor that exhibits the functional hallmarks of prototypical GPCRs

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.

Source: Signal Transduction Knowledge Environment - December 4, 2018 Category: Science Authors: Wright, S. C., Canizal, M. C. A., Benkel, T., Simon, K., Le Gouill, C., Matricon, P., Namkung, Y., Lukasheva, V., König, G. M., Laporte, S. A., Carlsson, J., Kostenis, E., Bouvier, M., Schulte, G., Hoffmann, C. Tags: STKE Research Articles Source Type: news