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PreprintCited by 92RNA and protein synthesis mechanismsRNA Research and SplicingPI3K/AKT/mTOR signaling in cancer

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The structure of a human translation initiation complex reveals two independent roles for the helicase eIF4A

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Querido, Jailson Brito, Sokabe, Masaaki, Díaz-López, Irene, Gordiyenko, Yuliya, Fraser, Christopher S., Ramakrishnan, V.·2022·Nature Structural & Molecular Biology
DOI 10.1101/2022.12.07.519490PMC PMC10948362

Preprint — published as 10.1038/s41594-023-01196-0

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Abstract

Summary: Initiation of mRNA translation is a key regulatory step in gene expression in all eukaryotes. Canonical initiation of translation in eukaryotes involves recruitment of the 43S preinitiation complex to the 5′ end of mRNA by the cap-binding complex eIF4F to form the 48S initiation complex (48S), followed by scanning along the mRNA until the start codon is selected.1–8 We have previously shown that eIF4F binds near the mRNA channel exit site of the 43S, leaving an open question about how mRNA secondary structure is removed as it enters the mRNA binding channel on the other side of the 40S subunit. 4 Here we describe a human 48S positioned at the start codon that shows that in addition to the eIF4A that is part of eIF4F, there is a second eIF4A helicase bound to the mRNA entry site. The entry channel bound eIF4A is positioned through interactions with eIF3 and the 40S subunit to enable its ATP-dependent helicase activity to directly unwind secondary structure located downstream of the scanning 48S complex. The structure also reveals universally conserved interactions between eIF4F and the 48S, likely explaining how this complex can promote mRNA recruitment in all eukaryotes. mRNA translation has emerged as an important tool for developing innovative therapies, yet several fundamental aspects of its regulation remain unknown. This work sheds light on the critical regulatory roles of eIF4A and eIF4F during the recruitment and scanning of the 5′ UTR of mRNA.

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Metadata

Authors
Querido, J. B., Sokabe, M., Díaz-López, I., Gordiyenko, Y., Fraser, C. S., & Ramakrishnan, V.
Affiliations
  • MRC Laboratory of Molecular Biology (GB)
  • University of California, Davis (US)
Corresponding author
  • Fraser, Christopher S.
  • Ramakrishnan, V.
ORCID
Venue
Nature Structural & Molecular Biology
Publisher
openRxiv
Published
2022-12-07
Volume
31
Issue
3
Pages
455-464
ISSN
1545-9985 (ISSN-L)
DOI
10.1101/2022.12.07.519490
PMC
PMC10948362
OpenAlex
W4391316948
Cited by
92
References
1
Citations by year
2026: 30 · 2025: 41 · 2024: 16 · 2023: 5
FWCI
11.81
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Nature Structural & Molecular Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nd)
Funders
  • Wellcome Trust (WT096570, 096570/Z/11/Z)
  • Louis-Jeantet Foundation
  • National Institutes of Health
  • Directorate for Biological Sciences
  • University of California, Davis
  • Medical Research Council (MC_U105184332)
  • Biotechnology and Biological Sciences Research Council
  • National Institute of General Medical Sciences (R01GM092927)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
translation initiation, 48S initiation complex, eIF4F, mRNA cap binding, 40S ribosomal subunit, human ribosome, protein complex structure
MeSH terms
DNA Helicases, Humans, Peptide Chain Initiation, Translational, Ribosomes, RNA, Messenger, Protein Biosynthesis, Codon, Initiator, Eukaryotic Initiation Factor-4F, Eukaryotic Initiation Factor-4A

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