Wnt acylation and its functional implication in Wnt signalling regulation

Abstract

Wnt proteins are conserved signalling molecules that have an essential role in regulating diverse processes during embryogenesis and adult tissue homoeostasis. Wnts are post-translationally modified by palmitoylation, which is essential for Wnt secretion and function. Intriguingly, the crystal structure of XWnt8 in complex with the extracellular domain of the Frizzled 8 cysteine-rich domain (Fzd8-CRD) revealed that Wnts use the fatty acid as a 'hotspot' residue to engage its receptor, which is a unique mode of receptor-ligand recognition. In addition, there are several lines of evidence suggesting that Wnts engage several signalling modulators and alternative receptors by means of fatty acids as a critical contact residue. In the present article, we review our current understanding of Wnt acylation and its functional role in Wnt signalling regulation.

Figure 1. Overall structure of Xenopus Wnt8 in complex with mouse Fzd8-CRD

N- and C-terminal domains of XWnt8 are colored in purple and red, respectively, Wnt O-linked palmitoylation in pink, and N-linked glycosylation in yellow. XWnt8 contacts the Fzd8-CRD (shown in green) through two independent binding sites located at the tips of the ‘thumb’ and ‘index finger’.

Figure 2. Demonstrated and putative Wnt-lipid-mediated interactions

Interactions of the Wnt palmitoylation with a) the CRD of Frizzled; b) the CRD of Ror2; c) the CRD of sFRP; d) the WIF domain of WIF-1; e) the cell membrane and f) the Wnt core to form a closed conformation are discussed. The crystal structure of sFRP3-CRD (wheat) revealed a hydrophobic Fzd-like lipid-binding groove, and the crystal structure of the WIF domain and EGF-like domains I–III of human WIF-1 (cyan) with bound phospholipid (pink) are shown.