作者
Yang Liu, Xiaofeng Qi, Linda Donnelly, Nadia Elghobashi-Meinhardt, Tao Long, Rich W Zhou, Yingyuan Sun, Boyuan Wang, Xiaochun Li
发表日期
2022/7
期刊
Nature
卷号
607
期号
7920
页码范围
816-822
出版商
Nature Publishing Group
简介
Wnt signalling is essential for regulation of embryonic development and adult tissue homeostasis, –, and aberrant Wnt signalling is frequently associated with cancers. Wnt signalling requires palmitoleoylation on a hairpin 2 motif by the endoplasmic reticulum-resident membrane-bound O-acyltransferase Porcupine, – (PORCN). This modification is indispensable for Wnt binding to its receptor Frizzled, which triggers signalling,. 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 trials; the complex with LGK974 and WNT3A hairpin 2 (WNT3Ap); and the complex with a synthetic palmitoleoylated WNT3Ap analogue. The structures reveal that hairpin 2 of WNT3A, which is well conserved in all Wnt ligands, inserts into PORCN from the …
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Y Liu, X Qi, L Donnelly, N Elghobashi-Meinhardt… - Nature, 2022