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Structural Basis for Activity Regulation of MLL Family Methyltransferases

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, etc.

Nature. 2016 Feb 25;530(7591):447-52.

PMID: 26886794

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42416111	MLL1/WDR5/Ash2L/RbBP5 human			Price
IAR42416121	Ash2L human			Price

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