Recognition of modification status on a histone H3 tail by linked histone reader modules of the epigenetic regulator UHRF1
Recognition of modification status on a histone H3 tail by linked histone reader modules of the epigenetic regulator UHRF1
复制标题
DOI：
10.1073/pnas.1203701109
复制
发表时间：
2012-08-07
影响因子：
11.1
通讯作者：
Shirakawa, Masahiro
中科院分区：
文献类型：
--
作者：
Arita, Kyohei;Isogai, Shin;Shirakawa, Masahiro
组蛋白尾部上的多个共价修饰通常被连接的组蛋白阅读器模块识别。UHRF 1 [ubiquitin-like，containing plant homeodomain（PHD）and really interesting new gene（RING）finger domains 1]是维持DNA甲基化的重要因子，包含两个连接的组蛋白阅读器模块，一个串联的Tudor结构域和一个PHD指，由一个17-aa的接头连接，并被认为与组蛋白修饰和DNA甲基化有关。在这里，我们提出了与组蛋白H3的氨基末端尾部复合的UHRF 1的连接组蛋白阅读器模块的晶体结构。我们的结构和生物化学数据提供了通过串联tudor结构域和PHD指组合读出未修饰的Arg-2（H3-R2）和甲基化的Lys-9（H3-K9）的基础。该结构揭示了模块间连接器通过与串联都铎结构域进行扩展接触，在阅读器模块之间形成组蛋白H3结合孔中起着至关重要的作用。组蛋白H3尾部通过采用包含中心螺旋的紧凑折叠而适合于孔，这允许两个读取器模块同时识别H3-R2和H3-K9处的修饰状态。我们的数据还表明，连接残基的磷酸化可以调节阅读模块的相对位置，从而改变组蛋白H3结合模式。这一发现意味着连接区作为UHRF 1的功能开关，参与多种调控途径，如DNA甲基化和转录抑制的维持。
Multiple covalent modifications on a histone tail are often recognized by linked histone reader modules. UHRF1 [ubiquitin-like, containing plant homeodomain (PHD) and really interesting new gene (RING) finger domains 1], an essential factor for maintenance of DNA methylation, contains linked two-histone reader modules, a tandem Tudor domain and a PHD finger, tethered by a 17-aa linker, and has been implicated to link histone modifications and DNA methylation. Here, we present the crystal structure of the linked histone reader modules of UHRF1 in complex with the amino-terminal tail of histone H3. Our structural and biochemical data provide the basis for combinatorial readout of unmodified Arg-2 (H3-R2) and methylated Lys-9 (H3-K9) by the tandem tudor domain and the PHD finger. The structure reveals that the intermodule linker plays an essential role in the formation of a histone H3-binding hole between the reader modules by making extended contacts with the tandem tudor domain. The histone H3 tail fits into the hole by adopting a compact fold harboring a central helix, which allows both of the reader modules to simultaneously recognize the modification states at H3-R2 and H3-K9. Our data also suggest that phosphorylation of a linker residue can modulate the relative position of the reader modules, thereby altering the histone H3-binding mode. This finding implies that the linker region plays a role as a functional switch of UHRF1 involved in multiple regulatory pathways such as maintenance of DNA methylation and transcriptional repression.