2. Academic Validation
  3. Structural basis for activity regulation of MLL family methyltransferases

Structural basis for activity regulation of MLL family methyltransferases

  • Nature. 2016 Feb 25;530(7591):447-52. doi: 10.1038/nature16952.
Yanjing Li 1 2,  Jianming Han 1 2,  Yuebin Zhang 3,  Fang Cao 4,  Zhijun Liu 1 2,  Shuai Li 5,  Jian Wu 1 2,  Chunyi Hu 1 2,  Yan Wang 1 2,  Jin Shuai 1 2,  Juan Chen 1 2,  Liaoran Cao 3,  Dangsheng Li 6,  Pan Shi 7,  Changlin Tian 7 8,  Jian Zhang 5,  Yali Dou 4,  Guohui Li 3,  Yong Chen 1 2,  Ming Lei 1 2
Affiliations

Affiliations

  • 1 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, 333 Haike Road, Shanghai 201210, China.
  • 2 Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China.
  • 3 Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, The Chinese Academy of Sciences, Dalian, Liaoning 116023, China.
  • 4 Department of Pathology, University of Michigan Medical School, 1301 Catherine, Ann Arbor, Michigan 48109, USA.
  • 5 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
  • 6 Shanghai Information Center for Life Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 7 High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, China.
  • 8 National Laboratory for Physical Science at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei 230026, China.
PMID: 26886794 DOI: 10.1038/nature16952
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.

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