MLLメチルトランスフェラーゼによる核子の認識と改変の構造的基礎
Han Xue1, Tonghui Yao1, Mi Cao2
1State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Nature
|September 6, 2019
まとめ
混合血統白血病 (MLL) タンパク質はヒストンH3K4をメチレートし,遺伝子調節に不可欠です. Cryo-EM構造は,MLL1およびMLL3複合体が核細胞とどのように相互作用し,ヒストンH2BのユビキチネーションによるH3K4メチル化と調節を説明する.
科学分野:
- エピジェネティクスと遺伝子調節
- 構造生物学
- ヒストン変化の分子メカニズム
背景:
- 混合血統白血病 (MLL) 家族のメチルトランスフェラーゼは,発達および細胞過程における転写調節に不可欠です.
- MLL酵素がH3K4メチル化マークを核細胞に蓄積する正確なメカニズムは,特にヒストンH2B全域化への反応として,まだ十分に理解されていません.
- MLLタンパク質は,WDR5,RBBP5,ASH2L,DPY30のような調節因子を持つ複合体の一部として機能する.
研究 の 目的:
- MLL1とMLL3の触媒モジュールの相互作用の構造的基礎を解明する.
- ヒストンH2Bモノウビキチネーション (H2BK120ub1) がMLL活性と核細胞結合にどのように影響するかを理解する.
- MLL1 と MLL3 の酵素活性における WDR5 の異なる調節作用を明らかにする.
主な方法:
- 高解像度構造を決定するために,冷凍電子顕微鏡 (cryo-EM) が使用されました.
- ヒトのMLL1とMLL3の触媒モジュールは,核素核粒子に結合した構造を得ました.
- 核粒子は未修正ヒストンH2BまたはH2BK120ub1を含んでいた.
主要な成果:
- MLL1とMLL3複合体は,核細胞のヒストン折れとDNAの両方と広範な相互作用を示し,H3K4メチル化のためのヒストンH3尾へのアクセスを容易にする.
- H2BK120ub1マークは,MLL複合体の重要な構成要素であるRBBP5と直接相互作用し,それによって酵素-核細胞結合を指向します.
- WDR5-RBBP5-MLLインターフェイスの異なる構造組織は,MLL1とMLL3の活動を制御するWDR5の対極的な役割を説明する.
結論:
- これらの発見は,MLL酵素が核細胞レベルでどのように調節されているかについての前例のない構造的な洞察を提供します.
- この研究では,MLLによるヒストンの尾の修正を指示するヒストンの改変を含む核細胞構造の重要な役割が強調されています.
- WDR5によるMLL1とMLL3の異なる調節は,表遺伝的制御メカニズムの複雑さを強調しています.
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