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

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. Ultimately, these studies lay the foundation necessary for proceeding toward a structural mechanism by which LARP1 links mTOR signalling to ribosome biogenesis.
 [1] ;  [1] ;  [2] ;  [3] ;  [4] ;  [4] ;  [1]
  1. Univ. of Pittsburgh, Pittsburgh, PA (United States)
  2. Brookhaven National Lab. (BNL), Upton, NY (United States)
  3. Univ. of Oxford, Oxford (United Kingdom)
  4. CNRS-UMR5096, Perpignan (France); Univ. de Perpignan-UMR5096, Perpignan (France)
Publication Date:
OSTI Identifier:
Report Number(s):
Journal ID: ISSN 0305-1048
Grant/Contract Number:
SC00112704; AC02-98CH10886; FWP BO-70; MWRIF 8059; 8P41GM103473-16
Accepted Manuscript
Journal Name:
Nucleic Acids Research
Additional Journal Information:
Journal Volume: 43; Journal Issue: 16; Journal ID: ISSN 0305-1048
Oxford University Press
Research Org:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States