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

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Peer-reviewed

Repository DOI


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Authors

Brito Querido, Jailson  ORCID logo  https://orcid.org/0000-0002-1438-1268
Díaz-López, Irene  ORCID logo  https://orcid.org/0000-0002-4703-4991
Gordiyenko, Yuliya 
Fraser, Christopher S  ORCID logo  https://orcid.org/0000-0001-9626-7743

Abstract

Eukaryotic translation initiation involves recruitment of the 43S pre-initiation complex to the 5' end of mRNA by the cap-binding complex eIF4F, forming the 48S translation initiation complex (48S), which then scans along the mRNA until the start codon is recognized. We have previously shown that eIF4F binds near the mRNA exit channel of the 43S, leaving open the question of how mRNA secondary structure is removed as it enters the mRNA channel on the other side of the 40S subunit. Here we report the structure of a human 48S that shows that, in addition to the eIF4A that is part of eIF4F, there is a second eIF4A helicase bound at the mRNA entry site, which could unwind RNA secondary structures as they enter the 48S. The structure also reveals conserved interactions between eIF4F and the 43S, probaby explaining how eIF4F can promote mRNA recruitment in all eukaryotes.

Description

Acknowledgements: We thank the LMB and eBIC (proposal BI23268-52, funded by the Wellcome Trust, MRC and BBSRC) cryo-EM facilities for their support during data collection, and J. Grimmett and T. Darling for computing. We thank N. Desai and N. R. James for preparing the cell extract and 80S ribosomes from which J.B.Q. purified the 40S small ribosomal subunits. We also thank J. Lorsch, T. Dever, A. Hinnebusch and V. Chandrasekaran for feedback on the manuscript. J.B.Q. was supported by an FEBS long-term fellowship; I.D.-L. was supported by an EMBO Postdoctoral Fellowship; V.R. was supported by the UK Medical Research Council (MC_U105184332), a Wellcome Trust Investigator award (WT096570) and the Louis-Jeantet Foundation; C.S.F. was supported by the NIH (grant R01 GM092927) and a seed grant for international collaboration from Global Affairs and the College of Biological Sciences at the University of California, Davis.

Keywords

Humans, Eukaryotic Initiation Factor-4F, Peptide Chain Initiation, Translational, RNA, Messenger, Codon, Initiator, Ribosomes, DNA Helicases, Protein Biosynthesis, Eukaryotic Initiation Factor-4A

Journal Title

Nat Struct Mol Biol

Conference Name

Journal ISSN

1545-9993
1545-9985

Volume Title

31

Publisher

Springer Science and Business Media LLC