来自额外的性状蛋白质PHD域的非传统结构和功能
Cameron J Reddington1, Annabel R Walsh1, Torsten Kleffmann1,2
1Biochemistry Department, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
ASXL PHD 域不结合组 histone H3 标记,而是通过复合结合点与 MBD5 或 MBD6 形成稳定的复合体,揭示了一种新的 PR-DUB 复合相互作用. 这一发现重新定义了这些域在表观遗传调节中的功能.
科学领域:
- 生物化学 生物化学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 结构生物学 结构生物学
背景情况:
- 聚抑制-脱基因酶 (PR-DUB) 复合体通过去除H2AK119Ub.Ub来调节基因表达.
- ASXL蛋白 (ASXL1-3) 是PR-DUB的核心组成部分,其C端植物宿主群 (PHD) 域涉及质子结合.
- 在癌症中,ASXL PHD域经常被截断,它们的相互作用伙伴MBD5和MBD6以前被认为可以结合甲基化DNA.
研究的目的:
- 研究ASXL PHD域在PR-DUB复合体中的功能作用.
- 确定ASXL PHD域与MBD5/MBD6.6之间的交互机制.
- 为了澄清ASXL PHD和MBD5/MBD6域的绑定能力.
主要方法:
- 在ASXL PHD域的AlphaFold3结构建模.
- 在体外生化测试以评估蛋白质与蛋白质相互作用和结合.
- 对ASXL PHD-MBD5和ASXL PHD-MBD6复合物的结构分析.
主要成果:
- ASXL PHD 域缺少 histone H3 的结合能力,并且不识别 histone 的表观遗传标记.
- ASXL PHD 域表现出非典型的折叠,并在体外结合单个离子.
- 在ASXL PHD和MBD5或MBD6之间形成稳定的复合体,它们的接口处由复合结位介导.
- 与之前的注释相反,MBD5和MBD6不结合甲基化DNA.
结论:
- 该ASXL PHD域的功能非正规,与MBD5或MBD6合作,而不是结合基因组尾巴.
- 一个新的复合材料结位点对于PR-DUB复合物的稳定性和功能至关重要.
- 这些发现修订了对PR-DUB复合组合的理解,以及ASXL,MBD5和MBD6在表观遗传调节中的作用.
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