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Structural basis for activity regulation of MLL family methyltransferases

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  • Yanjing Li

    (National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    Shanghai Science Research Center, Chinese Academy of Sciences)

  • Jianming Han

    (National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    Shanghai Science Research Center, Chinese Academy of Sciences)

  • Yuebin Zhang

    (Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, The Chinese Academy of Sciences)

  • Fang Cao

    (University of Michigan Medical School, 1301 Catherine)

  • Zhijun Liu

    (National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    Shanghai Science Research Center, Chinese Academy of Sciences)

  • Shuai Li

    (Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai JiaoTong University School of Medicine)

  • Jian Wu

    (National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    Shanghai Science Research Center, Chinese Academy of Sciences)

  • Chunyi Hu

    (National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    Shanghai Science Research Center, Chinese Academy of Sciences)

  • Yan Wang

    (National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    Shanghai Science Research Center, Chinese Academy of Sciences)

  • Jin Shuai

    (National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    Shanghai Science Research Center, Chinese Academy of Sciences)

  • Juan Chen

    (National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    Shanghai Science Research Center, Chinese Academy of Sciences)

  • Liaoran Cao

    (Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, The Chinese Academy of Sciences)

  • Dangsheng Li

    (Shanghai Information Center for Life Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences)

  • Pan Shi

    (High Magnetic Field Laboratory, Chinese Academy of Sciences)

  • Changlin Tian

    (High Magnetic Field Laboratory, Chinese Academy of Sciences
    National Laboratory for Physical Science at the Microscale and School of Life Sciences, University of Science and Technology of China)

  • Jian Zhang

    (Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai JiaoTong University School of Medicine)

  • Yali Dou

    (University of Michigan Medical School, 1301 Catherine)

  • Guohui Li

    (Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, The Chinese Academy of Sciences)

  • Yong Chen

    (National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    Shanghai Science Research Center, Chinese Academy of Sciences)

  • Ming Lei

    (National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    Shanghai Science Research Center, Chinese Academy of Sciences)

Abstract

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.

Suggested Citation

  • Yanjing Li & Jianming Han & Yuebin Zhang & Fang Cao & Zhijun Liu & Shuai Li & Jian Wu & Chunyi Hu & Yan Wang & Jin Shuai & Juan Chen & Liaoran Cao & Dangsheng Li & Pan Shi & Changlin Tian & Jian Zhang, 2016. "Structural basis for activity regulation of MLL family methyltransferases," Nature, Nature, vol. 530(7591), pages 447-452, February.
    • Handle: RePEc:nat:nature:v:530:y:2016:i:7591:d:10.1038_nature16952
    DOI: 10.1038/nature16952
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