文献类型：期刊文献

英文题名：Structural basis for product specificities of MLL family methyltransferases

作者：Li, Yanjing[1,2];Zhao, Lijie[1,3];Zhang, Yuebin[4];Wu, Ping[5];Xu, Ying[1];Mencius, Jun[2];Zheng, Yongxin[2];Wang, Xiaoman[1,3];Xu, Wancheng[1,3];Huang, Naizhe[1,3];Ye, Xianwen[6];Lei, Ming[7];Shi, Pan[8];Tian, Changlin[8];Peng, Chao[5];Li, Guohui[4];Liu, Zhijun[5];Quan, Shu[2];Chen, Yong[1,3,6]

机构：[1]Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Natl Ctr Prot Sci Shanghai, Ctr Excellence Mol Cell Sci,State Key Lab Mol Biol, Shanghai 200031, Peoples R China;[2]East China Univ Sci & Technol, Shanghai Collaborat Innovat Ctr Biomfg, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[3]Univ Chinese Acad Sci, Beijing 100049, Peoples R China;[4]Chinese Acad Sci, Dalian Inst Chem Phys, Lab Mol Modeling & Design, State Key Lab Mol React Dynam, Dalian 116023, Liaoning, Peoples R China;[5]Chinese Acad Sci, Shanghai Adv Res Inst, Zhangjiang Lab, Natl Facil Prot Sci Shanghai, Shanghai 201210, Peoples R China;[6]ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China;[7]Shanghai Jiao Tong Univ, Peoples Hosp 9, Shanghai Inst Precis Med, Sch Med, Shanghai 200025, Peoples R China;[8]Univ Sci & Technol China, Affiliated Hosp USTC 1, Joint Ctr Biol Analyt Chem, Sch Life Sci,Div Life Sci & Med,Anhui Engn Lab Pep, Hefei 230026, Peoples R China

年份：2022

卷号：82

期号：20

起止页码：3810

外文期刊名：MOLECULAR CELL

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000880784300010)】；

基金：We thank staff members of the BL19U1 beamline of the National Facility for Protein Science Shanghai (NFPS) at Shanghai Synchrotron Radiation Facility for X-ray diffraction data collection. We are grateful to the staff members of the mass spectrometry system, the nuclear magnetic resonance system, and the large-scale protein production system of NFPS for providing technical support. This work was supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB37010303 to Y.C.) , the Shanghai Pilot Program for Basic Research - CAS Shanghai Branch (JCYJ-SHFY-2022-008 to Y.C.) , the National Natural Science Foundation of China (31670748 and 31970576 to Y.C., 32071195 and 31900934 to Y.L., 21933010 to G.L., and 31700647 to Y.Z.) , the Young Elite Scientist Sponsorship Program by CAST (YESS20170198 to Y.L.) , the National Postdoctoral Program for Innovative Talents (BX201700263 to Y.L.) , the Construction and Operation of Zhangjiang Laboratory (II) (19DZ2260100 to C.P.) , the National Key R&D Program of China (2019YFA0709400 to G.L.) , and the maintenance and reconstruction project (DSS-WXGZ-2020-0001 to C.P.) .

语种：英文

摘要：Human mixed-lineage leukemia (MLL) family methyltransferases methylate histone H3 lysine 4 to different methylation states (me1/me2/me3) with distinct functional outputs, but the mechanism underlying the different product specificities of MLL proteins remains unclear. Here, we develop methodologies to quantitatively measure the methylation rate difference between mono-, di-, and tri-methylation steps and demonstrate that MLL proteins possess distinct product specificities in the context of the minimum MLL-RBBP5-ASH2L complex. Comparative structural analyses of MLL complexes by X-ray crystal structures, fluorine-19 nuclear magnetic resonance, and molecular dynamics simulations reveal that the dynamics of two conserved tyrosine residues at the "F/Y (phenylalanine/tyrosine) switch"positions fine-tune the product specificity. The variation in the intramolecular interaction between SET-N and SET-C affects the F/Y switch dynamics, thus determining the product specificities of MLL proteins. These results indicate a modified F/Y switch rule applicable for most SET domain methyltransferases and implicate the functional divergence of MLL proteins.