典型文献
Cholesterylation of Smoothened is a calcium-accelerated autoreaction involving an intramolecular ester intermediate
文献摘要：
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 modified or activated by cholesterol.The homozygous SmoD99E/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.
文献关键词：
中图分类号：
作者姓名：
Ao Hu;Jing-Zan Zhang;Jie Wang;Chen-Chen Li;Meng Yuan;Gang Deng;Zi-Cun Lin;Zhi-Ping Qiu;Hu-Yue Liu;Xian-Wei Wang;Peng-Cheng Wei;Xiao He;Xiaolu Zhao;Wen-Wei Qiu;Bao-Liang Song
作者机构：
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;Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development,School of Chemistry and Molecular Engineering,East China Normal University,Shanghai,China;College of Science,Zhejiang University of Technology,Hangzhou,Zhejiang,China;NYU-ECNU Center for Computational Chemistry at NYU Shanghai,Shanghai,China
文献出处：
引用格式：
[1]Ao Hu;Jing-Zan Zhang;Jie Wang;Chen-Chen Li;Meng Yuan;Gang Deng;Zi-Cun Lin;Zhi-Ping Qiu;Hu-Yue Liu;Xian-Wei Wang;Peng-Cheng Wei;Xiao He;Xiaolu Zhao;Wen-Wei Qiu;Bao-Liang Song-.Cholesterylation of Smoothened is a calcium-accelerated autoreaction involving an intramolecular ester intermediate)[J].细胞研究（英文版）,2022(03):288-301
A类：
Cholesterylation,autoreaction,cholesterylation,incompetent,D95E,SmoD99E,D99E
B类：
Smoothened,calcium,accelerated,involving,intramolecular,intermediate,Hedgehog,Hh,morphogen,that,binds,its,receptor,Patched,activates,SMO,thereby,governing,embryonic,postnatal,tissue,homeostasis,Cholesterol,covalently,conjugate,luminal,cysteine,rich,domain,CRD,human,residue,mouse,mechanism,biological,function,have,been,elucidated,Here,we,show,undergoes,which,boosted,involves,In,cells,stimulation,elevates,concentration,localized,endosomes,through,store,operated,entry,addition,identify,signaling,mutation,mutant,cholesterol,but,cannot,modified,activated,homozygous,knockin,mice,are,lethal,severe,developmental,delay,demonstrating,required,full,length,activation,Our,work,reveals,unique,autocatalytic,unprecedented,role
AB值：
0.515826
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