生物
形态发生剂
内质网
酰基转移酶
细胞生物学
跨膜蛋白
生物化学
音猬因子
刺猬信号通路
信号转导
酶
受体
基因
作者
Claire E. Coupland,Sebastian A. Andrei,T. Bertie Ansell,L. Carrique,Pramod Kumar,Lea Sefer,Rebekka A. Schwab,Eamon F.X. Byrne,Els Pardon,Jan Steyaert,Anthony I. Magee,Thomas Lanyon‐Hogg,Mark S.P. Sansom,E.W. Tate,Christian Siebold
出处
期刊:Molecular Cell
[Elsevier]
日期:2021-12-01
卷期号:81 (24): 5025-5038.e10
被引量:24
标识
DOI:10.1016/j.molcel.2021.11.018
摘要
The Sonic Hedgehog (SHH) morphogen pathway is fundamental for embryonic development and stem cell maintenance and is implicated in various cancers. A key step in signaling is transfer of a palmitate group to the SHH N terminus, catalyzed by the multi-pass transmembrane enzyme Hedgehog acyltransferase (HHAT). We present the high-resolution cryo-EM structure of HHAT bound to substrate analog palmityl-coenzyme A and a SHH-mimetic megabody, revealing a heme group bound to HHAT that is essential for HHAT function. A structure of HHAT bound to potent small-molecule inhibitor IMP-1575 revealed conformational changes in the active site that occlude substrate binding. Our multidisciplinary analysis provides a detailed view of the mechanism by which HHAT adapts the membrane environment to transfer an acyl chain across the endoplasmic reticulum membrane. This structure of a membrane-bound O-acyltransferase (MBOAT) superfamily member provides a blueprint for other protein-substrate MBOATs and a template for future drug discovery.
科研通智能强力驱动
Strongly Powered by AbleSci AI