Cholesterylation of Smoothened is a calcium-accelerated autoreaction involving an intramolecular ester intermediate

查看全文 作　　者：Ao [1]Hu;Jing-Zan [2]Zhang;Jie [2]Wang;Chen-Chen [2]Li;Meng [1]Yuan;Gang [1]Deng;Zi-Cun [1]Lin;Zhi-Ping [1]Qiu;Hu-Yue [1]Liu;Xian-Wei [2,3]Wang;Peng-Cheng [1]Wei;Xiao [2,4]He;Xiaolu [1]Zhao;Wen-Wei [2]Qiu;Bao-Liang [1]Song

机构地区：[1]The Institute for Advanced Studies,Hubei Key Laboratory of Cell Homeostasis,College of Life Sciences,TaiKang Center for Life and Medical Sciences,TaiKang Medical School,Wuhan University,Wuhan,Hubei,China;[2]Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development,School of Chemistry and Molecular Engineering,East China Normal University,Shanghai,China;[3]College of Science,Zhejiang University of Technology,Hangzhou,Zhejiang,China;[4]NYU-ECNU Center for Computational Chemistry at NYU Shanghai,Shanghai,China

出　　处：《Cell Research》索引2022年第32卷第3期,共14页

基　　金：We thank Ms.Dan Liang for technical assitance,Dr.Wei Qi(ShanghaiTech University)for revising the manuscript.We appreciate the helpful discussion with Drs.Guo-Yin Yin Wuhan University)and Yun Zhao(Shanghail Istitutes for Biological Sciences);This work was supported by grants from the National Natural Science Foundation of China(22077035,91753204,31690102,91957103);Ministry of Science and Technology of China(2018YF A0800700.2019YFA0802701);Fountain-Valley Life Sciences Fund of University of Chinese Academy of Sciences Education Foundation.B.-L.S.acknowledges the support from the Tencent Foundation through the XPLORER PRIZE. 摘　　要：Hedgehog(Hh)is a morphogen that binds to its receptor Patched 1 and activates Smoothened(SMO),thereby governing embryonic development and postnatal tissue homeostasis.Cholesterol can bind and covalently conjugate to the luminal cysteine-rich domain(CRD)of human SMO at the D95 residue(D99 in mouse).The reaction mechanism and biological function of SMO cholesterylation have not been elucidated.Here,we show that the SMO-CRD undergoes auto cholesterylation which is boosted by calcium and involves an intramolecular ester intermediate.In cells,Hh stimulation elevates local calcium concentration in the SMO-localized endosomes through store-operated calcium entry.In addition,we identify the signaling-incompetent SMO D95E mutation,and the D95E mutant SMO can bind cholesterol but cannot be modifed or activated by cholesterol.The homozygous Smo^(O99E/D99E) knockin mice are embryonic lethal with severe developmental delay,demonstrating that cholesterylation of CRD is required for full-length SMO activation.Our work reveals the unique autocatalytic mechanism of SMO cholesterylation and an unprecedented role of calcium in Hh signaling. 关键词：SMOOTHENED CHOLESTEROL stimulation

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Cholesterylation of Smoothened is a calcium-accelerated autoreaction involving an intramolecular ester intermediate

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