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Prespliceosome structure provides insights into spliceosome assembly and regulation

机译：前剪接体结构提供了对剪接体组装和调控的见解

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The spliceosome catalyses the excision of introns from pre-mRNA in two steps, branching and exon ligation, and is assembled from five small nuclear ribonucleoprotein particles (snRNPs; Ul, U2, U4, U5, U6) and numerous non-snRNP factors'. For branching, the intron 5' splice site and the branch point sequence are selected and brought by the U1 and U2 snRNPs into the prespliceosome(1),which is a focal point for regulation by alternative splicing factors(2). The U4/U6.U5 tri-snRNP subsequently joins the prespliceosome to form the complete pre-catalytic spliceosome. Recent studies have revealed the structural basis of the branching and exon-ligation reactions(3), however, the structural basis of the early events in spliceosome assembly remains poorly understood(4). Here we report the cryo-electron microscopy structure of the yeast Saccharomyces cerevisiae prespliceosome at near-atomic resolution. The structure reveals an induced stabilization of the 5' splice site in the Ul snRNP, and provides structural insights into the functions of the human alternative splicing factors LUC7-like (yeast Luc7) and TIA-1 (yeast Nam8), both of which have been linked to human disease(5,6). In the prespliceosome, the U1 snRNP associates with the U2 snRNP through a stable contact with the U2 3' domain and a transient yeast-specific contact with the U2 SF3b-containing 5' region, leaving its tri-snRNP-binding interface fully exposed. The results suggest mechanisms for 5' splice site transfer to the U6 ACAGAGA region within the assembled spliceosome and for its subsequent conversion to the activation-competent B-complex spliceosome(7,8). Taken together, the data provide a working model to investigate the early steps of spliceosome assembly.
机译：剪接体在两个步骤中（分支和外显子连接）催化从mRNA前体中切除内含子，并由五个小的核糖核蛋白颗粒（snRNP； U1，U2，U4，U5，U6）和许多非snRNP因子组装而成。对于分支，选择内含子5'剪接位点和分支点序列，并由U1和U2 snRNPs带入prespliceosome（1），prespliceosome（1）是通过其他剪接因子调节的焦点（2）。随后，U4 / U6.U5 tri-snRNP加入前剪接体，形成完整的预催化剪接体。最近的研究揭示了分支和外显子连接反应的结构基础（3），但是，对剪接体组装中的早期事件的结构基础仍然知之甚少（4）。在这里，我们报告酵母酿酒酵母prespliceosome在近原子分辨率的低温电子显微镜结构。该结构揭示了Ul snRNP中5'剪接位点的诱导稳定性，并提供了对人类替代剪接因子LUC7-like（酵母Luc7）和TIA-1（酵母Nam8）的功能的结构见解。与人类疾病有关（5,6）。在剪接前体中，U1 snRNP通过与U2 3'结构域的稳定接触以及与含U2 SF3b的5'区的瞬时酵母特异性接触而与U2 snRNP缔合，从而使其tri-snRNP结合界面完全暴露。结果提示了5'剪接位点转移到组装的剪接体中的U6 ACAGAGA区域并随后转换为具有激活功能的B复合剪接体的机制（7,8）。两者合计，这些数据提供了一个工作模型来研究剪接体组装的早期步骤。

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  • 来源
    《Nature》 |2018年第7714期|419-422|共4页
  • 作者

    Plaschka Clemens; Lin Pei-Chun; Charenton Clement; Nagai Kiyoshi;

  • 作者单位

    MRC Lab Mol Biol, Cambridge, England;

    MRC Lab Mol Biol, Cambridge, England;

    MRC Lab Mol Biol, Cambridge, England;

    MRC Lab Mol Biol, Cambridge, England;

  • 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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