小柯机器人

上海交大黄晶组揭示MLL识别核小体的结构基础
2019-09-05 15:59

上海交通大学医学院附属第九人民医院黄晶研究组利用冷冻电镜揭示了MLL甲基转移酶识别和修饰核小体的结构基础。2019年9月4日,《自然》在线发表了这一成果。

研究人员报道了人类MLL1和MLL3催化模块与核小体核心颗粒结合的冷冻电镜结构,包含H2BK120ub1(组蛋白H2B在赖氨酸第120位上的单泛素化)或未修饰的H2BK120。这些结构证明MLL1和MLL3复合物都与核小体的组蛋白折叠和DNA区域广泛接触;这样可以容易接触组蛋白H3尾部,这对于H3K4的有效甲基化至关重要。H2B上连接的泛素直接结合RBBP5,指导MLL1或MLL3与核小体之间的结合。MLL1和MLL3复合物在WDR5、RBBP5和MLL1(或相应的MLL3)亚基之间的界面处显示不同的结构组织,这解释了WDR5在调节两种酶的活性中的相反作用。这些发现改变了人们对在核小体水平上调节MLL活性的结构基础的理解,并突出了核小体调控在组蛋白尾部修饰中的关键作用。

据介绍,混合谱系白血病(MLL)家族的甲基转移酶包括MLL1、MLL2、MLL3、MLL4、SET1A和SET1B,它们在组蛋白H3第4位赖氨酸(H3K4)上负责甲基化,并且在造血、脂肪生成和发育的转录调节中具有关键和独特的作用。MLL蛋白的C末端催化结构域SET(Su(var.)3-9, enhancer of zeste and trithorax)与一组共同的调节因子(WDR5、RBBP5、ASH2L和DPY30)结合,从而来实现特定的活性。目前关于MLL活性调节的认知仅限于组蛋白H3肽段的催化,并且对H3K4甲基标记如何富集在核小体上的认知甚少。组蛋白H2B在赖氨酸第120位上的单泛素化(H2BK120ub1,这是一种普遍的组蛋白H2B标记)激活H3K4甲基化,破坏染色质压缩并有利于开放的染色质结构,但潜在的机制仍然未知。

更多阅读

黄晶,上海交通大学医学院附属第九人民医院基础医学专业博士生导师。研究方向:肿瘤发生发展机制的结构生物学研究、非编码RNA与其蛋白质结合因子的结构生物学研究。(据上海交通大学医学院

附:英文原文

Title: Structural basis of nucleosome recognition and modification by MLL methyltransferases

Author: Han Xue, Tonghui Yao, Mi Cao, Guanjun Zhu, Yan Li, Guiyong Yuan, Yong Chen, Ming Lei, Jing Huang

Issue&Volume: 2019-09-04

Abstract: Methyltransferases of the mixed-lineage leukaemia (MLL) familywhich include MLL1, MLL2, MLL3, MLL4, SET1A and SET1Bimplement methylation of histone H3 on lysine 4 (H3K4), and have critical and distinct roles in the regulation of transcription in haematopoiesis, adipogenesis and development16. 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 activities79. 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 unknown1012. 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.

DOI: 10.1038/s41586-019-1528-1

Source:https://www.nature.com/articles/s41586-019-1528-1

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

分享到:

0