CryoEM structures of pseudouridine-free ribosome suggest impacts of chemical modifications on ribosome conformations.
CryoEM structures of pseudouridine-free ribosome suggest impacts of chemical modifications on ribosome conformations.
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DOI：
10.1016/j.str.2022.04.002
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发表时间：
2022-07-07
期刊：
影响因子：
5.7
通讯作者：
Li, Hong
中科院分区：
文献类型：
--
作者：
Zhao, Yu;Rai, Jay;Yu, Hongguo;Li, Hong
假尿嘧啶是最丰富的RNA修饰形式，已知在核糖体功能中起重要作用。人类DKC1（负责催化核糖体RNA修饰的伪尿嘧啶合成酶）的突变导致翻译缺陷，并与复杂的癌症易感性相关。假尿嘧啶如何影响核糖体功能的结构基础尚未确定。在这里，我们用电子冷冻显微镜对来自酿酒酵母的完全修饰和假尿嘧啶无核糖体在没有配体或与易位抑制剂环己亚胺结合时的结构和构象进行了表征。在修饰的核糖体中，观察到假尿嘧啶N1原子的重排通过与磷酸盐主链建立主要由水介导的密切接触来稳定关键的功能基序。然而，假尿嘧啶无核糖体缺乏这种相互作用，并显示反映异常亚基间运动的构象。假尿嘧啶无核糖体的错误运动可以解释其在翻译中观察到的缺陷。Zhao等人报道了用低温电镜对假尿嘧啶无酵母菌核糖体的结构表征，揭示了与天然核糖体的巨大构象差异。
Pseudouridine, the most abundant form of RNA modification, is known to play important roles in ribosome function. Mutations in human DKC1, the pseudouridine synthase responsible for catalyzing the ribosome RNA modification, cause translation deficiencies and are associated with a complex cancer predisposition. The structural basis for how pseudouridine impacts ribosome function remains uncharacterized. Here we characterized structures and conformations of a fully modified and a pseudouridine-free ribosome from Saccharomyces cerevisiae in absence of ligands or when bound with translocation inhibitor cycloheximide by electron cryomicroscopy. In the modified ribosome, the rearranged N1 atom of pseudouridine is observed to stabilize key functional motifs by establishing predominately water-mediated close contacts with the phosphate backbone. The pseudouridine-free ribosome, however, is devoid of such interactions and displays conformations reflective of abnormal inter-subunit movements. The erroneous motions of the pseudouridine-free ribosome may explain its observed deficiencies in translation. Zhao et al. report the structural characterization of pseudouridine-free yeast ribosome by cryoEM that reveals large conformational differences from the native ribosome.
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