Structural basis for activity regulation of MLL family methyltransferases

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; Yali Dou; Guohui Li; Yong Chen; Ming Lei

doi:10.1038/nature16952

Structural basis for activity regulation of MLL family methyltransferases

Nature. 2016 Feb 25;530(7591):447-52. doi: 10.1038/nature16952. Epub 2016 Feb 17.

Authors

Yanjing Li^{1

2}, Jianming Han^{1

2}, Yuebin Zhang³, Fang Cao⁴, Zhijun Liu^{1

2}, Shuai Li⁵, Jian Wu^{1

2}, Chunyi Hu^{1

2}, Yan Wang^{1

2}, Jin Shuai^{1

2}, Juan Chen^{1

2}, Liaoran Cao³, Dangsheng Li⁶, Pan Shi⁷, Changlin Tian^{7

8}, Jian Zhang⁵, Yali Dou⁴, Guohui Li³, Yong Chen^{1

2}, Ming Lei^{1

2}

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Crystallography, X-Ray
DNA-Binding Proteins / chemistry*
DNA-Binding Proteins / metabolism*
Enzyme Activation
Histone-Lysine N-Methyltransferase / chemistry*
Histone-Lysine N-Methyltransferase / genetics
Histone-Lysine N-Methyltransferase / metabolism*
Histones / metabolism
Humans
Intracellular Signaling Peptides and Proteins
Models, Molecular
Molecular Sequence Data
Multiprotein Complexes
Mutant Proteins / chemistry
Mutant Proteins / metabolism
Myeloid-Lymphoid Leukemia Protein / chemistry*
Myeloid-Lymphoid Leukemia Protein / genetics
Myeloid-Lymphoid Leukemia Protein / metabolism*
Nuclear Proteins / chemistry
Nuclear Proteins / metabolism
Protein Binding
Protein Structure, Quaternary
Protein Structure, Tertiary
Transcription Factors / chemistry
Transcription Factors / metabolism

Substances

ASH2L protein, human
DNA-Binding Proteins
Histones
Intracellular Signaling Peptides and Proteins
KMT2A protein, human
KMT2C protein, human
Multiprotein Complexes
Mutant Proteins
Nuclear Proteins
RBBP5 protein, human
Transcription Factors
WDR5 protein, human
Myeloid-Lymphoid Leukemia Protein
Histone-Lysine N-Methyltransferase

Associated data

PDB/5F59
PDB/5F5E
PDB/5F6K
PDB/5F6L

Grants and funding

R01 GM082856/GM/NIGMS NIH HHS/United States