2. Academic Validation
  3. The La-related protein 1-specific domain repurposes HEAT-like repeats to directly bind a 5'TOP sequence

The La-related protein 1-specific domain repurposes HEAT-like repeats to directly bind a 5'TOP sequence

  • Nucleic Acids Res. 2015 Sep 18;43(16):8077-88. doi: 10.1093/nar/gkv748.
Roni M Lahr 1,  Seshat M Mack 1,  Annie Héroux 2,  Sarah P Blagden 3,  Cécile Bousquet-Antonelli 4,  Jean-Marc Deragon 4,  Andrea J Berman 5
Affiliations

Affiliations

  • 1 Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
  • 2 Photon Sciences Directorate, Bldg 745 L107 Brookhaven National Laboratory Upton, NY 11973, USA.
  • 3 Department of Oncology, University of Oxford, Churchill Hospital, Oxford, OX3 7LE, UK.
  • 4 CNRS-UMR5096 LGDP, 66860 Perpignan, France Université de Perpignan-UMR5096 LGDP, 66860 Perpignan, France.
  • 5 Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA ajb190@pitt.edu.
PMID: 26206669 DOI: 10.1093/nar/gkv748
Abstract

La-related protein 1 (LARP1) regulates the stability of many mRNAs. These include 5'TOPs, mTOR-kinase responsive mRNAs with pyrimidine-rich 5' UTRs, which encode ribosomal proteins and translation factors. We determined that the highly conserved LARP1-specific C-terminal DM15 region of human LARP1 directly binds a 5'TOP sequence. The crystal structure of this DM15 region refined to 1.86 Å resolution has three structurally related and evolutionarily conserved helix-turn-helix modules within each monomer. These motifs resemble HEAT repeats, ubiquitous helical protein-binding structures, but their sequences are inconsistent with consensus sequences of known HEAT modules, suggesting this structure has been repurposed for RNA interactions. A putative mTORC1-recognition sequence sits within a flexible loop C-terminal to these repeats. We also present modelling of pyrimidine-rich single-stranded RNA onto the highly conserved surface of the DM15 region. These studies lay the foundation necessary for proceeding toward a structural mechanism by which LARP1 links mTOR signalling to ribosome biogenesis.

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