Journal Article

Structural basis for activity regulation of MLL family methyltransferases

Hu, Chunyi, Han, Jianming, Wu, Jian, Zhang, Jian, Shi, Pan, Dou, Yali, Zhang, Yuebin, Li, Shuai, Li, Guohui, Lei, Ming, Wang, Yan, Li, Yanjing, Cao, Fang, Liu, Zhijun, Tian, Changlin, Cao, Liaoran, Li, Dangsheng, Shuai, Jin, Chen, Yong, Chen, Juan

2016

Overview

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. Crystal structures of the SET domains of MLL3 and a mutant MLL1 either unbound or complexed with domains from RBBP5 and ASH2L are determined; a combination of structural, biochemical and computational analyses reveals a two-step activation mechanism of MLL family proteins, which may be relevant for other histone methyltransferases. Activation mechanism for MLL enzymes The SET domain-containing MLL family proteins methylate histone 3 on lysine 4 (H3K4) and have key roles in transcriptional regulation. MLL proteins are catalytically inactive on their own, and have full activity only when bound in a complex with three factors: WDR5, RBBP5, and ASH2L. Yong Chen and colleagues determine crystal structures of the SET domains of MLL3 and a mutant MLL1 in unbound forms or complexed with domains from RBBP5 and ASH2L and the histone H3 substrate. Their results suggest that WDR5 is not directly involved in enzymatic stimulation, and a combination of structural, biochemical and computational analyses reveals a two-step activation mechanism which may be relevant for all histone methyltransferases.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/176 / 631/337/100/2285 / 631/45/173 / 631/535/1266 / Amino Acid Sequence / Crystal structure / Crystallography, X-Ray / Development and progression / DNA-Binding Proteins - chemistry / DNA-Binding Proteins - metabolism / Enzyme Activation / Enzymes / Genetic aspects / Histone-Lysine N-Methyltransferase - chemistry / Histone-Lysine N-Methyltransferase - genetics / Histone-Lysine N-Methyltransferase - metabolism / Histones - metabolism / Humanities and Social Sciences / Humans / Leukemia / Methylation / Methyltransferases / Models, Molecular / Molecular Sequence Data / multidisciplinary / 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 / Peptides / Physiological aspects / Protein Binding / Protein Structure, Quaternary / Protein Structure, Tertiary / Proteins / Science / Transcription Factors - chemistry / Transcription Factors - metabolism