Structural basis for targeting the chromatin repressor Sfmbt to Polycomb response elements.
Structural basis for targeting the chromatin repressor Sfmbt to Polycomb response elements.
复制标题
将染色质阻遏蛋白 Sfmbt 靶向 Polycomb 响应元件的结构基础。
DOI：
10.1101/gad.226621.113
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发表时间：
2013-11-01
影响因子：
10.5
通讯作者：
Müller CW
中科院分区：
文献类型：
--
作者：
Alfieri C;Gambetta MC;Matos R;Glatt S;Sehr P;Fraterman S;Wilm M;Müller J;Müller CW
Polycomb group（PcG）复合物通过修饰它们的染色质来抑制发育调节基因。然而，PcG蛋白如何组装成复合物并被招募到其靶基因中的了解甚少。在这里，Alfieri等人报道了PcG复合物PhoRC核心的晶体结构，其中含有DNA结合蛋白Pho和辅阻遏物Sfmbt。作者表明，Pho对Polycomb反应元件的Sfmbt的束缚对于果蝇中发育调节基因的Polycomb抑制是必不可少的。这项研究揭示了PcG蛋白复合物在特定基因组位点组装的分子基础。Polycomb group（PcG）蛋白复合物通过修饰它们的染色质来抑制发育调节基因。不同的PcG蛋白如何组装成复合物并被招募到其靶基因中，目前还知之甚少。在这里，我们报告的晶体结构的核心果蝇PcG蛋白复合物Pleiohomeotic（Pho）-抑制复合物（PhoRC），其中包含Polycomb响应元件（PRE）结合蛋白Pho和Sfmbt。Pho的间隔区通过长的柔性接头与DNA结合结构域分开，与Sfmbt的四个恶性脑肿瘤（4 MBT）结构域形成紧密复合物。人Pho直系同源物YY 1的高度保守间隔区以类似的方式结合四种人4 MBT结构域蛋白中的三种，但亲和力较低。比较果蝇Pho：Sfmbt和人YY 1：MBTD 1复合物结构，为YY 1对人4 MBT结构域蛋白的低亲和力提供了分子解释。结构指导突变，破坏Pho和Sfmbt之间的相互作用，废除形成三元Sfmbt：Pho：DNA复合物在体外和抑制果蝇的发育调节基因。因此，通过Pho对Sfmbt的PRE拴系对于果蝇中的Polycomb抑制是必不可少的。我们的研究结果支持一个模型，其中DNA拴系的Sfmbt的Pho和多价的相互作用的Sfmbt与组蛋白修饰和其他PcG蛋白创建一个枢纽PcG蛋白复合物组装在PRE。
Polycomb group (PcG) complexes repress developmental regulator genes by modifying their chromatin. However, how PcG proteins assemble into complexes and are recruited to their target genes is poorly understood. Here, Alfieri et al. report the crystal structure of the core of the PcG complex PhoRC, which contains the DNA-binding protein Pho and corepressor Sfmbt. The authors show that tethering of Sfmbt by Pho to Polycomb response elements is essential for Polycomb repression of developmental regulator genes in Drosophila. This study thus reveals the molecular basis for PcG protein complex assembly at specific genomic sites. Polycomb group (PcG) protein complexes repress developmental regulator genes by modifying their chromatin. How different PcG proteins assemble into complexes and are recruited to their target genes is poorly understood. Here, we report the crystal structure of the core of the Drosophila PcG protein complex Pleiohomeotic (Pho)-repressive complex (PhoRC), which contains the Polycomb response element (PRE)-binding protein Pho and Sfmbt. The spacer region of Pho, separated from the DNA-binding domain by a long flexible linker, forms a tight complex with the four malignant brain tumor (4MBT) domain of Sfmbt. The highly conserved spacer region of the human Pho ortholog YY1 binds three of the four human 4MBT domain proteins in an analogous manner but with lower affinity. Comparison of the Drosophila Pho:Sfmbt and human YY1:MBTD1 complex structures provides a molecular explanation for the lower affinity of YY1 for human 4MBT domain proteins. Structure-guided mutations that disrupt the interaction between Pho and Sfmbt abolish formation of a ternary Sfmbt:Pho:DNA complex in vitro and repression of developmental regulator genes in Drosophila. PRE tethering of Sfmbt by Pho is therefore essential for Polycomb repression in Drosophila. Our results support a model where DNA tethering of Sfmbt by Pho and multivalent interactions of Sfmbt with histone modifications and other PcG proteins create a hub for PcG protein complex assembly at PREs.
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影响因子：
7.7
作者：
Grimm, Clemens;de Ayala Alonso, Andres Gaytan;Mueller, Christoph W.
通讯作者：
Mueller, Christoph W.
影响因子：
64.5
作者：
Czermin, B;Melfi, R;Pirrotta, V
通讯作者：
Pirrotta, V
影响因子：
11.4
作者：
Grimm, Clemens;Matos, Raquel;Ly-Hartig, Nga;Steuerwald, Ulrich;Lindner, Doris;Rybin, Vladimir;Mueller, Juerg;Mueller, Christoph W.
通讯作者：
Mueller, Christoph W.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
16
作者：
Cao, R;Tsukada, Y;Zhang, Y
通讯作者：
Zhang, Y