WNT signalling is a major pathway that is required for normal growth and development as it helps regulate cell proliferation and stem cell maintenance. It also underlies disease, with sustained and inappropriate activation the cause of excessive cell division and cancer. WNT signalling is activated upon interaction of the soluble WNT ligand with the Frizzled (FZD) receptor. Controlling the number of FZD receptors on the cell surface is a key negative feedback loop that helps regulate WNT signalling. Two RING E3 ligases, RNF43 and ZNRF3, promote the ubiquitination and internalisation of FZD, thereby turning off WNT signalling.
Here I will present data that reveals the molecular determinants of ubiquitin transfer by ZNRF3 and RNF43. Our data indicate that the RING domain is monomeric, and that RING dimerization is not required for its ubiquitin ligase activity. However, the ectodomain of ZNRF3 forms dimers and our data supports a model where the cytoplasmic domains self-associate in cells even though RING dimerization is not required for activity. We suggest that the arrangement of the cytoplasmic domains may influence substrate binding and ubiquitylation.