Direct β-arrestin engagement by the non-canonical WNT receptor FZD6 via a shallow binding pocket

As primary WNT receptors, Frizzled (FZD) receptors behave as nonclassical GPCRs; however, their engagement with downstream transducers is largely unknown. Previous studies have suggested that β-arrestin recruitment to FZD receptors depends on its interaction with Dishevelled (DVL) and that this process regulates both canonical and non-canonical pathways. Here, we reveal that FZD6, which mainly mediates non-canonical WNT signalling, directly binds to β-arrestin 1 (βarr1) and report the cryo-EM structure of the FZD6-βarr1 complex, which revealed a unique shallow pocket in FZD6 for βarr1 engagement and identified arrestin-specific motifs that are distinct from those observed in previously reported FZD receptor-transducer complexes. Collectively, our findings establish a direct arrestin recruitment mechanism in FZD receptors that shares key features with arrestin engagement in classical GPCRs, suggesting that the engagement of core GPCR transducers may modulate WNT signalling specificity. These insights position FZD receptors as druggable targets akin to classical GPCRs, opening new avenues for targeting FZD receptors for a wide range of diseases, including cancer.