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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.

Original publication

DOI

10.1093/nar/gkv748

Type

Journal article

Journal

Nucleic Acids Res

Publication Date

18/09/2015

Volume

43

Pages

8077 - 8088

Keywords

5' Untranslated Regions, Amino Acid Motifs, Amino Acid Sequence, Autoantigens, Conserved Sequence, Helix-Turn-Helix Motifs, Humans, Models, Molecular, RNA, Messenger, Repetitive Sequences, Amino Acid, Ribonucleoproteins, Static Electricity