La-related protein 1 (LARP1) binds the mRNA cap, blocking eIF4F assembly on TOP mRNAs

  1. Roni M Lahr
  2. Bruno D Fonseca
  3. Gabrielle E Ciotti
  4. Hiba A Al-Ashtal
  5. Jian-Jun Jia
  6. Marius R Niklaus
  7. Sarah P Blagden
  8. Tommy Alain
  9. Andrea J Berman  Is a corresponding author
  1. University of Pittsburgh, United States
  2. Children's Hospital of Eastern Ontario Research Institute, Canada
  3. 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

The following data sets were generated
    1. Lahr and Berman
    (2017) DM15-RNA cocrystal
    Publicly available at the RCSB Protein Data Bank (accession no: 5V7C).
    1. Lahr and Berman
    (2017) DM15-m7GTP cocrystal
    Publicly available at the RCSB Protein Data Bank (accession no: 5V4R).
    1. Lahr and Berman
    (2017) DM15-m7GpppC cocrystal
    Publicly available at the RCSB Protein Data Bank (accession no: 5V87).

Article and author information

Author details

  1. Roni M Lahr

    Department of Biological Sciences, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Bruno D Fonseca

    Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Gabrielle E Ciotti

    Department of Biological Sciences, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Hiba A Al-Ashtal

    Department of Biological Sciences, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jian-Jun Jia

    Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Marius R Niklaus

    Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Sarah P Blagden

    Department of Oncology, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Tommy Alain

    Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  9. Andrea J Berman

    Department of Biological Sciences, University of Pittsburgh, Pittsburgh, United States
    For correspondence
    ajb190@pitt.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1217-7412

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

  1. Cynthia Wolberger, Johns Hopkins University, United States

Publication history

  1. Received: December 11, 2016
  2. Accepted: April 4, 2017
  3. Accepted Manuscript published: April 5, 2017 (version 1)
  4. Accepted Manuscript updated: April 7, 2017 (version 2)
  5. 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.

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  1. Roni M Lahr
  2. Bruno D Fonseca
  3. Gabrielle E Ciotti
  4. Hiba A Al-Ashtal
  5. Jian-Jun Jia
  6. Marius R Niklaus
  7. Sarah P Blagden
  8. Tommy Alain
  9. Andrea J Berman
(2017)
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

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