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

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. Ultimately, these studies lay the foundation necessary for proceeding toward a structural mechanism by which LARP1 links mTOR signalling to ribosome biogenesis.

Authors:
 [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:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1229454
Report Number(s):
BNL-111530-2015-JA
Journal ID: ISSN 0305-1048
Grant/Contract Number:  
SC00112704; AC02-98CH10886; FWP BO-70; MWRIF 8059; 8P41GM103473-16
Resource Type:
Accepted Manuscript
Journal Name:
Nucleic Acids Research
Additional Journal Information:
Journal Volume: 43; Journal Issue: 16; Journal ID: ISSN 0305-1048
Publisher:
Oxford University Press
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Lahr, Roni M., Mack, Seshat M., Heroux, Annie, Blagden, Sarah P., Bousquet-Antonelli, Cecile, Deragon, Jean -Marc, and Berman, Andrea J. The La-related protein 1-specific domain repurposes HEAT-like repeats to directly bind a 5'TOP sequence. United States: N. p., 2015. Web. doi:10.1093/nar/gkv748.
Lahr, Roni M., Mack, Seshat M., Heroux, Annie, Blagden, Sarah P., Bousquet-Antonelli, Cecile, Deragon, Jean -Marc, & Berman, Andrea J. The La-related protein 1-specific domain repurposes HEAT-like repeats to directly bind a 5'TOP sequence. United States. doi:10.1093/nar/gkv748.
Lahr, Roni M., Mack, Seshat M., Heroux, Annie, Blagden, Sarah P., Bousquet-Antonelli, Cecile, Deragon, Jean -Marc, and Berman, Andrea J. Wed . "The La-related protein 1-specific domain repurposes HEAT-like repeats to directly bind a 5'TOP sequence". United States. doi:10.1093/nar/gkv748. https://www.osti.gov/servlets/purl/1229454.
@article{osti_1229454,
title = {The La-related protein 1-specific domain repurposes HEAT-like repeats to directly bind a 5'TOP sequence},
author = {Lahr, Roni M. and Mack, Seshat M. and Heroux, Annie and Blagden, Sarah P. and Bousquet-Antonelli, Cecile and Deragon, Jean -Marc and Berman, Andrea J.},
abstractNote = {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.},
doi = {10.1093/nar/gkv748},
journal = {Nucleic Acids Research},
number = 16,
volume = 43,
place = {United States},
year = {2015},
month = {7}
}

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    Works referencing / citing this record:

    The LARP1 La-Module recognizes both ends of TOP mRNAs
    journal, October 2019