A complex IRES at the 5'-UTR of a viral mRNA assembles a functional 48S complex via an uAUG intermediate

Abstract
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Abstract

Taking control of the cellular apparatus for protein production is a requirement for virus progression. To ensure this control, diverse strategies of cellular mimicry and/or ribosome hijacking evolved. The initiation stage of translation is specially targeted as it involves multiple steps and the engagement of numerous initiation factors. The use of structured RNA sequences, called Internal Ribosomal Entry Sites (IRES) in viral RNAs is a widespread strategy for the exploitation of eukaryotic initiation. Using a combination of electron cryo-microscopy (cryo-EM) and reconstituted translation initiation assays with native components, we characterized how a novel IRES at the 5'-UTR of a viral RNA assembles a functional initiation complex via an uAUG intermediate. The IRES features a novel extended, multi-domain architecture, circling the 40S head. The structures and accompanying functional data, illustrate the importance of 5'-UTR regions in translation regulation and underline the relevance of the untapped diversity of viral IRESs.

Data availability

Atomic coordinates have been deposited in the PDB with accession numbers and 6W2S and 6W2T. CryoEM maps have been deposited at the EMDB with accession numbers EMDB 21529/21530

The following data sets were generated

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Ritam Neupane

Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-4787-279X
Vera P Pisareva

Department of Cell Biology, SUNY Downstate Medical Center, New York, United States

Competing interests
The authors declare that no competing interests exist.
Carlos F Rodriguez

Structural Biology Program, CNIO, Madrid, Spain

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9166-0132
Andrey V Pisarev

Department of Cell Biology, SUNY Downstate Medical Center, New York, United States

For correspondence
andrey.pisarev@downstate.edu

Competing interests
The authors declare that no competing interests exist.
Israel S Fernández

Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States

For correspondence
isf2106@cumc.columbia.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7218-1603

Funding

Columbia University (Start package)

Israel S Fernández

National Institute of General Medical Sciences (GM097014)

Andrey V Pisarev

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.