title: Structural basis for activity regulation of MLL family methyltransferases.
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.
authors.affiliation: 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.|Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China.
authors.forename: Yanjing
authors.initials: Y
authors.lastname: Li
authors.affiliation: 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.|Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China.
authors.forename: Jianming
authors.initials: J
authors.lastname: Han
authors.affiliation: 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.
authors.forename: Yuebin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Michigan Medical School, 1301 Catherine, Ann Arbor, Michigan 48109, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Cao
authors.affiliation: 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.|Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Shuai
authors.initials: S
authors.lastname: Li
authors.affiliation: 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.|Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.affiliation: 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.|Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China.
authors.forename: Chunyi
authors.initials: C
authors.lastname: Hu
authors.affiliation: 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.|Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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.|Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Shuai
authors.affiliation: 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.|Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Liaoran
authors.initials: L
authors.lastname: Cao
authors.affiliation: Shanghai Information Center for Life Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Dangsheng
authors.initials: D
authors.lastname: Li
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Shi
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, China.|National Laboratory for Physical Science at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei 230026, China.
authors.forename: Changlin
authors.initials: C
authors.lastname: Tian
authors.affiliation: 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.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Michigan Medical School, 1301 Catherine, Ann Arbor, Michigan 48109, USA.
authors.forename: Yali
authors.initials: Y
authors.lastname: Dou
authors.affiliation: 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.
authors.forename: Guohui
authors.initials: G
authors.lastname: Li
authors.affiliation: 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.|Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 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.|Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D004789:Enzyme Activation; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D051788:Myeloid-Lymphoid Leukemia Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism
chemical_list: C485622:ASH2L protein, human; D004268:DNA-Binding Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C497422:KMT2A protein, human; C452979:KMT2C protein, human; D046912:Multiprotein Complexes; D050505:Mutant Proteins; D009687:Nuclear Proteins; C470552:RBBP5 protein, human; D014157:Transcription Factors; C502547:WDR5 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase