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A conformational switch in HP1 releases auto-inhibition to drive heterochromatin assembly

机译:HP1中的构象开关释放自动抑制功能以驱动异染色质组装

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摘要

A hallmark of histone H3 lysine 9 (H3K9)-methylated heterochromatin, conserved from the fission yeast Schizosaccharomyces pombe to humans, is its ability to spread to adjacent genomic regions. Central to heterochromatin spread is heterochromatin protein 1 (HP1), which recognizes H3K9-methylated chromatin, oligomerizes and forms a versatile platform that participates in diverse nuclear functions, ranging from gene silencing to chromosome segregation. How HP1 proteins assemble on methylated nucleosomal templates and how the HP1-nucleosome complex achieves functional versatility remain poorly understood. Here we show that binding of the key S. pombe HP1 protein, Swi6, to methylated nudeosomes drives a switch from an auto-inhibited state to a spreading-competent state. In the auto-inhibited state, a histone-mimic sequence in one Swi6 monomer blocks methyl-mark recognition by the chromodomain of another monomer. Auto-inhibition is relieved by recognition of two template features, the H3K9 methyl mark and nucleosomal DNA. Cryo-electron-microscopy-based reconstruction of the Swi6-nucleosome complex provides the overall architecture of the spreading-competent state in which two unbound chromodomain sticky ends appear exposed. Disruption of the switch between the auto-inhibited and spreading-competent states disrupts heterochromatin assembly and gene silencing in vivo. These findings are reminiscent of other conditionally activated polymerization processes, such as actin nucleation, and open up a new class of regulatory mechanisms that operate on chromatin in vivo.
机译:从裂变酵母粟酒裂殖酵母对人保守的组蛋白H3赖氨酸9(H3K9)-甲基化异染色质的标志是其扩散到邻近基因组区域的能力。异染色质扩散的核心是异染色质蛋白1(HP1),它识别H3K9甲基化的染色质,寡聚并形成一个通用平台,参与从基因沉默到染色体分离等多种核功能。 HP1蛋白如何组装在甲基化的核小体模板上,以及HP1-核小体复合物如何实现功能通用性仍然知之甚少。在这里,我们显示了关键的粟酒裂殖酵母HP1蛋白Swi6与甲基化的核糖体的结合驱动了从自抑制状态到具有扩散能力的状态的转换。在自动抑制状态下,一个Swi6单体中的组蛋白模拟序列可通过另一单体的色域来阻止甲基标记识别。通过识别两个模板功能(H3K9甲基标记和核小体DNA)可以缓解自动抑制。 Swi6-核小体复合物的基于冷冻电子显微镜的重建提供了具有扩散能力的状态的整体架构,其中两个未结合的染色体结构域粘性末端似乎暴露在外。在自抑制状态和有扩散能力的状态之间切换的中断会破坏异染色质的组装和体内基因沉默。这些发现使人联想到其他有条件激活的聚合过程,例如肌动蛋白成核,并开启了在体内对染色质起作用的新型调节机制。

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  • 来源
    《Nature》 |2013年第7445期|377-381|共5页
  • 作者单位

    Department of Biochemistry and Biophysics, University of California San Francisco. California 94158. USA,Chemistry and Chemical Biology Graduate Program University of California San Francisco, California 94158, USA;

    Department of Biochemistry and Biophysics, University of California San Francisco. California 94158. USA;

    Department of Biochemistry and Biophysics, University of California San Francisco. California 94158. USA;

    Voiland School of Chemical Engineering and Bioengineering, Washington State University, Pullman, Washington 99164, USA;

    Department of Biochemistry and Biophysics, University of California San Francisco. California 94158. USA,Tetrad Graduate Program University of California San Francisco, California 94158, USA;

    Department of Biochemistry and Biophysics, University of California San Francisco. California 94158. USA;

    Department of Biochemistry and Biophysics, University of California San Francisco. California 94158. USA,Tetrad Graduate Program University of California San Francisco, California 94158, USA;

    Department of Biochemistry and Biophysics, University of California San Francisco. California 94158. USA,Tetrad Graduate Program University of California San Francisco, California 94158, USA;

    Department of Biochemistry and Biophysics, University of California San Francisco. California 94158. USA;

    Department of Biochemistry and Biophysics, University of California San Francisco. California 94158. USA;

    National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892, USA;

    Department of Biochemistry and Biophysics, University of California San Francisco. California 94158. USA;

    Department of Biochemistry and Biophysics, University of California San Francisco. California 94158. USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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