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致病原生动物与其哺乳动物宿主之间翻译起始的结构差异。

Structural Differences in Translation Initiation between Pathogenic Trypanosomatids and Their Mammalian Hosts.

机构信息

INSERM U1212 (ARNA), Institut Européen de Chimie et Biologie, Université de Bordeaux, Pessac 33607, France.

INSERM U1212 (ARNA), Institut Européen de Chimie et Biologie, Université de Bordeaux, Pessac 33607, France; CNRS UPR9002 (ARN), Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Strasbourg 67000, France.

出版信息

Cell Rep. 2020 Dec 22;33(12):108534. doi: 10.1016/j.celrep.2020.108534.

DOI:10.1016/j.celrep.2020.108534
PMID:33357443
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7773551/
Abstract

Canonical mRNA translation in eukaryotes begins with the formation of the 43S pre-initiation complex (PIC). Its assembly requires binding of initiator Met-tRNA and several eukaryotic initiation factors (eIFs) to the small ribosomal subunit (40S). Compared to their mammalian hosts, trypanosomatids present significant structural differences in their 40S, suggesting substantial variability in translation initiation. Here, we determine the structure of the 43S PIC from Trypanosoma cruzi, the parasite causing Chagas disease. Our structure shows numerous specific features, such as the variant eIF3 structure and its unique interactions with the large rRNA expansion segments (ESs) 9, 7, and 6, and the association of a kinetoplastid-specific DDX60-like helicase. It also reveals the 40S-binding site of the eIF5 C-terminal domain and structures of key terminal tails of several conserved eIFs underlying their activities within the PIC. Our results are corroborated by glutathione S-transferase (GST) pull-down assays in both human and T. cruzi and mass spectrometry data.

摘要

真核生物的规范 mRNA 翻译起始于 43S 起始复合物（PIC）的形成。其组装需要起始 Met-tRNA 和几种真核起始因子（eIFs）与小核糖体亚基（40S）结合。与它们的哺乳动物宿主相比，锥虫在其 40S 中表现出显著的结构差异，这表明翻译起始存在很大的可变性。在这里，我们确定了引起恰加斯病的寄生虫克氏锥虫的 43S PIC 的结构。我们的结构显示了许多特定的特征，例如变体 eIF3 结构及其与大 rRNA 扩展片段（ESs）9、7 和 6 的独特相互作用，以及动基体特异性 DDX60 样解旋酶的关联。它还揭示了 eIF5 C 末端结构域的 40S 结合位点，以及 PIC 中关键保守 eIF 末端尾巴的结构，这些结构是它们在 PIC 中活性的基础。我们的结果通过人源和 T. cruzi 的谷胱甘肽 S-转移酶（GST）下拉测定和质谱数据得到了证实。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1414/7773551/e471a3a62d92/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1414/7773551/841c52ccc597/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1414/7773551/0a283e448229/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1414/7773551/905880f7ce22/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1414/7773551/e37398bf8b4a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1414/7773551/457f93299e2a/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1414/7773551/9c6719b002cf/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1414/7773551/6d18f3b34480/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1414/7773551/e471a3a62d92/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1414/7773551/841c52ccc597/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1414/7773551/0a283e448229/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1414/7773551/905880f7ce22/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1414/7773551/e37398bf8b4a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1414/7773551/457f93299e2a/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1414/7773551/9c6719b002cf/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1414/7773551/6d18f3b34480/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1414/7773551/e471a3a62d92/gr7.jpg

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