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

Canonical mRNA translation in eukaryotes begins with the formation of the 43S pre-initiation complex (PIC). Its assembly requires binding of initiator Met-tRNA(i)(Met) and several eukaryotic initiation factors (eIFs) to the small ribosomal subunit (40S). Compared to their mammalian hosts, trypanosom...

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Autores principales: Bochler, Anthony, Querido, Jailson Brito, Prilepskaja, Terezie, Soufari, Heddy, Simonetti, Angelita, Del Cistia, Mayara Lucia, Kuhn, Lauriane, Ribeiro, Aline Rimoldi, Valášek, Leoš Shivaya, Hashem, Yaser
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773551/
https://www.ncbi.nlm.nih.gov/pubmed/33357443
http://dx.doi.org/10.1016/j.celrep.2020.108534
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author Bochler, Anthony
Querido, Jailson Brito
Prilepskaja, Terezie
Soufari, Heddy
Simonetti, Angelita
Del Cistia, Mayara Lucia
Kuhn, Lauriane
Ribeiro, Aline Rimoldi
Valášek, Leoš Shivaya
Hashem, Yaser
author_facet Bochler, Anthony
Querido, Jailson Brito
Prilepskaja, Terezie
Soufari, Heddy
Simonetti, Angelita
Del Cistia, Mayara Lucia
Kuhn, Lauriane
Ribeiro, Aline Rimoldi
Valášek, Leoš Shivaya
Hashem, Yaser
author_sort Bochler, Anthony
collection PubMed
description Canonical mRNA translation in eukaryotes begins with the formation of the 43S pre-initiation complex (PIC). Its assembly requires binding of initiator Met-tRNA(i)(Met) 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(S), 7(S), and 6(S), 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.
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spelling pubmed-77735512021-01-05 Structural Differences in Translation Initiation between Pathogenic Trypanosomatids and Their Mammalian Hosts Bochler, Anthony Querido, Jailson Brito Prilepskaja, Terezie Soufari, Heddy Simonetti, Angelita Del Cistia, Mayara Lucia Kuhn, Lauriane Ribeiro, Aline Rimoldi Valášek, Leoš Shivaya Hashem, Yaser Cell Rep Article Canonical mRNA translation in eukaryotes begins with the formation of the 43S pre-initiation complex (PIC). Its assembly requires binding of initiator Met-tRNA(i)(Met) 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(S), 7(S), and 6(S), 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. Cell Press 2020-12-22 /pmc/articles/PMC7773551/ /pubmed/33357443 http://dx.doi.org/10.1016/j.celrep.2020.108534 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Bochler, Anthony
Querido, Jailson Brito
Prilepskaja, Terezie
Soufari, Heddy
Simonetti, Angelita
Del Cistia, Mayara Lucia
Kuhn, Lauriane
Ribeiro, Aline Rimoldi
Valášek, Leoš Shivaya
Hashem, Yaser
Structural Differences in Translation Initiation between Pathogenic Trypanosomatids and Their Mammalian Hosts
title Structural Differences in Translation Initiation between Pathogenic Trypanosomatids and Their Mammalian Hosts
title_full Structural Differences in Translation Initiation between Pathogenic Trypanosomatids and Their Mammalian Hosts
title_fullStr Structural Differences in Translation Initiation between Pathogenic Trypanosomatids and Their Mammalian Hosts
title_full_unstemmed Structural Differences in Translation Initiation between Pathogenic Trypanosomatids and Their Mammalian Hosts
title_short Structural Differences in Translation Initiation between Pathogenic Trypanosomatids and Their Mammalian Hosts
title_sort structural differences in translation initiation between pathogenic trypanosomatids and their mammalian hosts
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773551/
https://www.ncbi.nlm.nih.gov/pubmed/33357443
http://dx.doi.org/10.1016/j.celrep.2020.108534
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