La-related protein 1 (LARP1) binds the mRNA cap, blocking eIF4F assembly on TOP mRNAs
- University of Pittsburgh, United States
- Children's Hospital of Eastern Ontario Research Institute, Canada
- University of Oxford, United Kingdom
Abstract
The 5’terminal oligopyrimidine (5’TOP) motif is a cis-regulatory RNA element located immediately downstream of the 7-methyl-guanosine [m7G] cap of TOP mRNAs, which encode ribosomal proteins and translation factors. In eukaryotes, this motif coordinates the synchronous and stoichiometric expression of the protein components of the translation machinery. La-related protein 1 (LARP1) binds TOP mRNAs, regulating their stability and translation. We present crystal structures of the human LARP1 DM15 region in complex with a 5’TOP motif, a cap analog (m7GTP), and a capped cytosine (m7GpppC) resolved to 2.6, 1.8 and 1.7 Å, respectively. Our binding, competition, and immunoprecipitation data corroborate and elaborate on the mechanism of 5’TOP motif binding by LARP1. We show that LARP1 directly binds the cap and adjacent 5’TOP motif of TOP mRNAs, effectively impeding access of eIF4E to the cap and preventing eIF4F assembly. Thus, LARP1 is a specialized TOP mRNA cap-binding protein that controls ribosome biogenesis.
Data availability
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DM15-RNA cocrystalPublicly available at the RCSB Protein Data Bank (accession no: 5V7C).
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DM15-m7GTP cocrystalPublicly available at the RCSB Protein Data Bank (accession no: 5V4R).
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DM15-m7GpppC cocrystalPublicly available at the RCSB Protein Data Bank (accession no: 5V87).
Article and author information
Author details
Funding
National Institute of General Medical Sciences (R01GM116889)
- Andrea J Berman
Prostate Cancer Canada (PCC Discovery Grant D2015-02)
- Bruno D Fonseca
- Tommy Allain
University of Pittsburgh
- Roni M Lahr
- Gabrielle E Ciotti
- Hiba A Al-Ashtal
- Andrea J Berman
Samuel and Emma Winters Foundation
- Andrea J Berman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, Lahr et al.
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.
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La-related protein 1 (LARP1) binds the mRNA cap, blocking eIF4F assembly on TOP mRNAs
eLife 6:e24146.
https://doi.org/10.7554/eLife.24146
