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
-
DM15-RNA cocrystalPublicly available at the RCSB Protein Data Bank (accession no: 5V7C).
-
DM15-m7GTP cocrystalPublicly available at the RCSB Protein Data Bank (accession no: 5V4R).
-
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
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.
Reviewing Editor
- Cynthia Wolberger, Johns Hopkins University, United States
Version history
- Received: December 11, 2016
- Accepted: April 4, 2017
- Accepted Manuscript published: April 5, 2017 (version 1)
- Accepted Manuscript updated: April 7, 2017 (version 2)
- Version of Record published: May 5, 2017 (version 3)
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.
Metrics
-
- 7,622
- views
-
- 1,303
- downloads
-
- 137
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
Further reading
-
- Biochemistry and Chemical Biology
- Chromosomes and Gene Expression
Recent findings indicate that the translation elongation rate influences mRNA stability. One of the factors that has been implicated in this link between mRNA decay and translation speed is the yeast DEAD-box helicase Dhh1p. Here, we demonstrated that the human ortholog of Dhh1p, DDX6, triggers the deadenylation-dependent decay of inefficiently translated mRNAs in human cells. DDX6 interacts with the ribosome through the Phe-Asp-Phe (FDF) motif in its RecA2 domain. Furthermore, RecA2-mediated interactions and ATPase activity are both required for DDX6 to destabilize inefficiently translated mRNAs. Using ribosome profiling and RNA sequencing, we identified two classes of endogenous mRNAs that are regulated in a DDX6-dependent manner. The identified targets are either translationally regulated or regulated at the steady-state-level and either exhibit signatures of poor overall translation or of locally reduced ribosome translocation rates. Transferring the identified sequence stretches into a reporter mRNA caused translation- and DDX6-dependent degradation of the reporter mRNA. In summary, these results identify DDX6 as a crucial regulator of mRNA translation and decay triggered by slow ribosome movement and provide insights into the mechanism by which DDX6 destabilizes inefficiently translated mRNAs.
-
- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
The articles in this special issue highlight how modern cellular, biochemical, biophysical and computational techniques are allowing deeper and more detailed studies of allosteric kinase regulation.
