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Dynamics of ribosome scanning and recycling revealed by translation complex profiling

机译：翻译复合体分析揭示了核糖体扫描和回收的动力学

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摘要

Regulation of messenger RNA translation is central to eukaryotic gene expression control(1). Regulatory inputs are specified by the mRNA untranslated regions (UTRs) and often target translation initiation. Initiation involves binding of the 40S ribosomal small subunit (SSU) and associated eukaryotic initiation factors (eIFs) near the mRNA 5' cap; the SSU then scans in the 3' direction until it detects the start codon and is joined by the 60S ribosomal large subunit (LSU)(2-5) to form the 80S ribosome. Scanning and other dynamic aspects of the initiation model have remained as conjectures because methods to trap early intermediates were lacking. Here we uncover the dynamics of the complete translation cycle in live yeast cells using translation complex profile sequencing (TCP-seq), a method developed from the ribosome profiling(6) approach. We document scanning by observing SSU footprints along 5' UTRs. Scanning SSU have 5'-extended footprints (up to similar to 75 nucleotides), indicative of additional interactions with mRNA emerging from the exit channel, promoting forward movement. We visualized changes in initiation complex conformation as SSU footprints coalesced into three major sizes at start codons (19, 29 and 37 nucleotides). These share the same 5' start site but differ at the 3' end, reflecting successive changes at the entry channel from an open to a closed state following start codon recognition. We also observe SSU 'lingering' at stop codons after LSU departure. Our results underpin mechanistic models of translation initiation and termination, built on decades of biochemical and structural investigation, with direct genome-wide in vivo evidence. Our approach captures ribosomal complexes at all phases of translation and will aid in studying translation dynamics in diverse cellular contexts. Dysregulation of translation is common in disease and, for example, SSU scanning is a target of anti-cancer drug development(7). TCP-seq will prove useful in discerning differences in mRNA-specific initiation in pathologies and their response to treatment.
机译：信使RNA翻译的调控是真核基因表达控制的核心（1）。调节输入由mRNA非翻译区（UTR）指定，通常以翻译起始为目标。起始涉及mRNA 5'帽附近的40S核糖体小亚基（SSU）和相关的真核起始因子（eIFs）的结合。然后，SSU沿3'方向扫描，直到检测到起始密码子为止，并与60S核糖体大亚基（LSU）（2-5）结合形成80S核糖体。由于缺少捕获早期中间体的方法，因此引发模型的扫描和其他动态方面仍然是一个推测。在这里，我们使用翻译复合体序列测序（TCP-seq），从核糖体分析（6）方法发展而来，揭示了活酵母细胞中完整翻译循环的动力学。我们通过观察5'UTR上的SSU足迹来记录扫描。扫描SSU具有5'延伸的足迹（最多类似于75个核苷酸），表明与从出口通道出来的mRNA发生了额外的相互作用，从而促进了向前运动。随着SSU足迹在起始密码子（19、29和37个核苷酸）上合并为三个主要大小，我们观察到起始复合物构象的变化。它们共享相同的5'起始位点，但在3'端不同，反映了在起始密码子识别后进入通道从打开状态到关闭状态的连续变化。我们还观察到LSU出发后，SSU在停留密码子处“徘徊”。我们的研究结果基于数十年的生化和结构研究以及直接的全基因组体内证据，为翻译起始和终止的力学模型提供了基础。我们的方法可在翻译的所有阶段捕获核糖体复合物，并将有助于研究不同细胞环境中的翻译动力学。翻译异常在疾病中很常见，例如，SSU扫描是抗癌药物开发的目标（7）。 TCP-seq将有助于识别病理学中的mRNA特异性起始差异及其对治疗的反应。

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  • 来源
    《Nature》 |2016年第7613期|570-574|共5页
  • 作者

    Archer Stuart K.; Shirokikh Nikolay E.; Beilharz Traude H.; Preiss Thomas;

  • 作者单位

    Australian Natl Univ, John Curtin Sch Med Res, Dept Genome Sci, EMBL Australia Collaborating Grp, Canberra, ACT 2601, Australia|Monash Univ, Monash Bioinformat Platform, Melbourne, Vic 3800, Australia;

    Australian Natl Univ, John Curtin Sch Med Res, Dept Genome Sci, EMBL Australia Collaborating Grp, Canberra, ACT 2601, Australia|Moscow Reg State Inst Humanities & Social Studies, Kolomna 140410, Russia;

    Monash Univ, Monash Biomed Discovery Inst, Dev & Stem Cells Program, Melbourne, Vic 3800, Australia|Monash Univ, Dept Biochem & Mol Biol, Melbourne, Vic 3800, Australia;

    Australian Natl Univ, John Curtin Sch Med Res, Dept Genome Sci, EMBL Australia Collaborating Grp, Canberra, ACT 2601, Australia|Victor Chang Cardiac Res Inst, Darlinghurst, NSW 2010, Australia;

  • 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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