Mechanisms and inhibition of Porcupine-mediated Wnt acylation.

ABSTRACT: Wnt signalling is essential for regulation of embryonic development and adult tissue homeostasis^1-3, and aberrant Wnt signalling is frequently associated with cancers⁴. Wnt signalling requires palmitoleoylation on a hairpin 2 motif by the endoplasmic reticulum-resident membrane-bound O-acyltransferase Porcupine^5-7 (PORCN). This modification is indispensable for Wnt binding to its receptor Frizzled, which triggers signalling^8,9. Here we report four cryo-electron microscopy structures of human PORCN: the complex with the palmitoleoyl-coenzyme A (palmitoleoyl-CoA) substrate; the complex with the PORCN inhibitor LGK974, an anti-cancer drug currently in clinical trials¹⁰; the complex with LGK974 and WNT3A hairpin 2 (WNT3Ap); and the complex

SUBMITTER: Liu Y 

PROVIDER: S-EPMC9404457 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature