Structural basis for activity regulation of MLL family methyltransferases.
Structural basis for activity regulation of MLL family methyltransferases.
复制标题
MLL家族甲基转移酶活性调节的结构基础
DOI：
10.1038/nature16952
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发表时间：
2016-02-25
期刊：
影响因子：
64.8
通讯作者：
Lei, Ming
中科院分区：
文献类型：
--
作者：
Li, Yanjing;Han, Jianming;Zhang, Yuebin;Cao, Fang;Liu, Zhijun;Li, Shuai;Wu, Jian;Hu, Chunyi;Wang, Yan;Shuai, Jin;Chen, Juan;Cao, Liaoran;Li, Dangsheng;Shi, Pan;Tian, Changlin;Zhang, Jian;Dou, Yali;Li, Guohui;Chen, Yong;Lei, Ming
混合谱系白血病（MLL）蛋白家族（包括MLL 1-MLL 4、SET 1A和SET 1B）特异性甲基化组蛋白3Lys 4，并且在涉及造血和发育的基因的转录调控中具有关键作用。MLL 1的甲基转移酶活性本身严重受损，受到所有MLL家族复合物共有的三个保守因子WDR 5、RBBP 5和ASH 2L的刺激。然而，这些因素如何调节MLL蛋白的活性的分子机制仍然知之甚少。在这里，我们表明，一个最小化的人类RBBP 5-ASH 2L异二聚体的结构单元，相互作用，并激活所有MLL家族组蛋白甲基转移酶。我们的结构，生物化学和计算分析揭示了MLL家族蛋白的两步激活机制。这些发现为MLL家族甲基转移酶在复杂组装和活性调节中的共同主题和功能可塑性提供了前所未有的见解，也表明了大多数组蛋白甲基转移酶的普遍调节机制。
The mixed lineage leukaemia (MLL) family of proteins (including MLL1–MLL4, SET1A and SET1B) specifically methylate histone 3 Lys4, and have pivotal roles in the transcriptional regulation of genes involved in haematopoiesis and development. The methyltransferase activity of MLL1, by itself severely compromised, is stimulated by the three conserved factors WDR5, RBBP5 and ASH2L, which are shared by all MLL family complexes. However, the molecular mechanism of how these factors regulate the activity of MLL proteins still remains poorly understood. Here we show that a minimized human RBBP5–ASH2L heterodimer is the structural unit that interacts with and activates all MLL family histone methyltransferases. Our structural, biochemical and computational analyses reveal a two-step activation mechanism of MLL family proteins. These findings provide unprecedented insights into the common theme and functional plasticity in complex assembly and activity regulation of MLL family methyltransferases, and also suggest a universal regulation mechanism for most histone methyltransferases.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
16
作者：
Southall, Stacey M.;Wong, Poon-Sheng;Wilson, Jon R.
通讯作者：
Wilson, Jon R.
影响因子：
14.9
作者：
Lindahl E;Azuara C;Koehl P;Delarue M
通讯作者：
Delarue M
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1126/science.1198056
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Parsons DW;Li M;Zhang X;Jones S;Leary RJ;Lin JC;Boca SM;Carter H;Samayoa J;Bettegowda C;Gallia GL;Jallo GI;Binder ZA;Nikolsky Y;Hartigan J;Smith DR;Gerhard DS;Fults DW;VandenBerg S;Berger MS;Marie SK;Shinjo SM;Clara C;Phillips PC;Minturn JE;Biegel JA;Judkins AR;Resnick AC;Storm PB;Curran T;He Y;Rasheed BA;Friedman HS;Keir ST;McLendon R;Northcott PA;Taylor MD;Burger PC;Riggins GJ;Karchin R;Parmigiani G;Bigner DD;Yan H;Papadopoulos N;Vogelstein B;Kinzler KW;Velculescu VE
通讯作者：
Velculescu VE