eIF1A residues implicated in cancer stabilize translation preinitiation complexes and favor suboptimal initiation sites in yeast

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Abstract

The translation pre-initiation complex (PIC) scans the mRNA for an AUG codon in favorable context, and AUG recognition stabilizes a closed PIC conformation. The unstructured N-terminal tail (NTT) of yeast eIF1A deploys five basic residues to contact tRNA_i, mRNA, or 18S rRNA exclusively in the closed state. Interestingly, EIF1AX mutations altering the human eIF1A NTT are associated with uveal melanoma (UM). We found that substituting all five basic residues, and seven UM-associated substitutions, in yeast eIF1A suppresses initiation at near-cognate UUG codons and AUGs in poor context. Ribosome profiling of NTT substitution R13P reveals heightened discrimination against unfavorable AUG context genome-wide. Both R13P and K16D substitutions destabilize the closed complex at UUG codons in reconstituted PICs. Thus, electrostatic interactions involving the eIF1A NTT stabilize the closed conformation and promote utilization of suboptimal start codons. We predict UM-associated mutations alter human gene expression by increasing discrimination against poor initiation sites.

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The following data sets were generated

(2017) eIF1A residues implicated in cancer stabilize translation preinitiation complexes and favor suboptimal initiation sites in yeast
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http://www.ncbi.nlm.nih.gov/geo/

The following previously published data sets were used

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Pilar Martin-Marcos

Laboratory on the Mechanism and Regulation of Protein Synthesis, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States

Competing interests
No competing interests declared.
Fujun Zhou

Laboratory on the Mechanism and Regulation of Protein Synthesis, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States

Competing interests
No competing interests declared.
Charm Karunasiri

Laboratory on the Mechanism and Regulation of Protein Synthesis, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States

Competing interests
No competing interests declared.
Fan Zhang

Laboratory of Gene Regulation and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States

Competing interests
No competing interests declared.
Jinsheng Dong

Laboratory of Gene Regulation and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States

Competing interests
No competing interests declared.
Jagpreet Nanda

Laboratory on the Mechanism and Regulation of Protein Synthesis, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States

Competing interests
No competing interests declared.
Neelam Sen

Laboratory of Gene Regulation and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States

Competing interests
No competing interests declared.
Mercedes Tamame

Instituto de Biología Funcional y Genómica (IBFG-CSIC)), Universidad de Salamanca, Salamanca, Spain

Competing interests
No competing interests declared.
Michael Zeschnigk

Institute of Human Genetics and Eye Cancer Research Group, University Duisburg-Essen, Essen, Germany

Competing interests
No competing interests declared.
Jon R Lorsch

Laboratory on the Mechanism and Regulation of Protein Synthesis, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States

For correspondence
jon.lorsch@nih.gov

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-4521-4999
Alan G Hinnebusch

Laboratory of Gene Regulation and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States

For correspondence
ahinnebusch@nih.gov

Competing interests
Alan G Hinnebusch, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0002-1627-8395

Funding

National Institutes of Health (Intramural Research Program)

Alan G Hinnebusch

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

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.