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Structure paper

タイトル	Structural basis of nucleosome recognition and modification by MLL methyltransferases.
ジャーナル・号・ページ	Nature, Vol. 573, Issue 7774, Page 445-449, Year 2019
掲載日	2019年9月4日
著者	Han Xue / Tonghui Yao / Mi Cao / Guanjun Zhu / Yan Li / Guiyong Yuan / Yong Chen / Ming Lei / Jing Huang /
PubMed 要旨	Methyltransferases of the mixed-lineage leukaemia (MLL) family-which include MLL1, MLL2, MLL3, MLL4, SET1A and SET1B-implement methylation of histone H3 on lysine 4 (H3K4), and have critical and ...Methyltransferases of the mixed-lineage leukaemia (MLL) family-which include MLL1, MLL2, MLL3, MLL4, SET1A and SET1B-implement methylation of histone H3 on lysine 4 (H3K4), and have critical and distinct roles in the regulation of transcription in haematopoiesis, adipogenesis and development. The C-terminal catalytic SET (Su(var.)3-9, enhancer of zeste and trithorax) domains of MLL proteins are associated with a common set of regulatory factors (WDR5, RBBP5, ASH2L and DPY30) to achieve specific activities. Current knowledge of the regulation of MLL activity is limited to the catalysis of histone H3 peptides, and how H3K4 methyl marks are deposited on nucleosomes is poorly understood. H3K4 methylation is stimulated by mono-ubiquitination of histone H2B on lysine 120 (H2BK120ub1), a prevalent histone H2B mark that disrupts chromatin compaction and favours open chromatin structures, but the underlying mechanism remains unknown. Here we report cryo-electron microscopy structures of human MLL1 and MLL3 catalytic modules associated with nucleosome core particles that contain H2BK120ub1 or unmodified H2BK120. These structures demonstrate that the MLL1 and MLL3 complexes both make extensive contacts with the histone-fold and DNA regions of the nucleosome; this allows ease of access to the histone H3 tail, which is essential for the efficient methylation of H3K4. The H2B-conjugated ubiquitin binds directly to RBBP5, orienting the association between MLL1 or MLL3 and the nucleosome. The MLL1 and MLL3 complexes display different structural organizations at the interface between the WDR5, RBBP5 and MLL1 (or the corresponding MLL3) subunits, which accounts for the opposite roles of WDR5 in regulating the activity of the two enzymes. These findings transform our understanding of the structural basis for the regulation of MLL activity at the nucleosome level, and highlight the pivotal role of nucleosome regulation in histone-tail modification.
リンク	Nature / PubMed:31485071
手法	EM (単粒子)
解像度	3.2 - 4.5 Å
構造データ	0693 6kiw EMDB-0693, PDB-6kiw: Cryo-EM structure of human MLL3-ubNCP complex (4.0 angstrom) 手法: EM (単粒子) / 解像度: 4.0 Å 0694 6kix EMDB-0694, PDB-6kix: Cryo-EM structure of human MLL1-NCP complex, binding mode1 手法: EM (単粒子) / 解像度: 4.1 Å 0695 6kiz EMDB-0695, PDB-6kiz: Cryo-EM structure of human MLL1-NCP complex, binding mode2 手法: EM (単粒子) / 解像度: 4.5 Å 9998 6kiu EMDB-9998, PDB-6kiu: Cryo-EM structure of human MLL1-ubNCP complex (3.2 angstrom) 手法: EM (単粒子) / 解像度: 3.2 Å 9999 6kiv EMDB-9999, PDB-6kiv: Cryo-EM structure of human MLL1-ubNCP complex (4.0 angstrom) 手法: EM (単粒子) / 解像度: 4.0 Å
化合物	ChemComp-SAH: S-ADENOSYL-L-HOMOCYSTEINE / S-アデノシルホモシステイン ChemComp-ZN: Unknown entry ChemComp-LYS: LYSINE / 2-アンモニオ-2-デアミノ-L-リシン ChemComp-GLN: GLUTAMINE / グルタミン
由来	homo sapiens (ヒト) xenopus laevis (アフリカツメガエル) synthetic construct (人工物)
キーワード	TRANSCRIPTION/DNA / histone modification / nucleosome / MLL / TRANSCRIPTION / TRANSCRIPTION-DNA complex