Structural Basis for the Requirement of Additional Factors for MLL1 SET Domain Activity and Recognition of Epigenetic Marks

被引:180
作者
Southall, Stacey M. [1 ]
Wong, Poon-Sheng [1 ]
Odho, Zain [1 ]
Roe, S. Mark [1 ]
Wilson, Jon R. [1 ]
机构
[1] Inst Canc Res, Chester Beatty Labs, Sect Struct Biol, London SW3 6JB, England
基金
英国医学研究理事会;
关键词
HISTONE METHYLTRANSFERASE SET7/9; MIXED LINEAGE LEUKEMIA; LYSINE-4; METHYLATION; GENE-EXPRESSION; MOLECULAR REGULATION; H3K4; TRIMETHYLATION; FUNCTIONAL-ANALYSIS; COMPLEX; MECHANISM; ROLES;
D O I
10.1016/j.molcel.2008.12.029
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The mixed-lineage leukemia protein MLL1 is a transcriptional regulator with an essential role in early development and hematopoiesis. The biological function of MLL1 is mediated by the histone H3K4 methyltransferase activity of the carboxyl-terminal SET domain. We have determined the crystal structure of the MLL1 SET domain in complex with cofactor product AdoHcy and a histone H3 peptide. This structure indicates that, in order to form a well ordered active site, a highly variable but essential component of the SET domain must be repositioned. To test this idea, we compared the effect of the addition of MLL complex members on methyltransferase activity and show that both RbBP5 and Ash2L but not Wdr5 stimulate activity. Additionally, we have determined the effect of posttranslational modifications on histone H3 residues downstream and upstream from the target lysine and provide a structural explanation for why H3T3 phosphorylation and H3K9 acetylation regulate activity.
引用
收藏
页码:181 / 191
页数:11
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