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. These studies lay the foundation necessary for proceeding toward a structural mechanism by which LARP1 links mTOR signalling to ribosome biogenesis.
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Roni M
authors.initials: RM
authors.lastname: Lahr
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Seshat M
authors.initials: SM
authors.lastname: Mack
authors.affiliation: Photon Sciences Directorate, Bldg 745 L107 Brookhaven National Laboratory Upton, NY 11973, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Héroux
authors.affiliation: Department of Oncology, University of Oxford, Churchill Hospital, Oxford, OX3 7LE, UK.
authors.forename: Sarah P
authors.initials: SP
authors.lastname: Blagden
authors.affiliation: CNRS-UMR5096 LGDP, 66860 Perpignan, France Université de Perpignan-UMR5096 LGDP, 66860 Perpignan, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Bousquet-Antonelli
authors.affiliation: CNRS-UMR5096 LGDP, 66860 Perpignan, France Université de Perpignan-UMR5096 LGDP, 66860 Perpignan, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Deragon
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA ajb190@pitt.edu.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Berman
mesh_terms: D020121:5' Untranslated Regions; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001324:Autoantigens / Q000737:chemistry* / Q000378:metabolism; D017124:Conserved Sequence; D019077:Helix-Turn-Helix Motifs; D006801:Humans; D008958:Models, Molecular; D012333:RNA, Messenger / Q000378:metabolism; D020449:Repetitive Sequences, Amino Acid; D012261:Ribonucleoproteins / Q000737:chemistry* / Q000378:metabolism; D055672:Static Electricity; D000097585:SS-B Antigen
chemical_list: D020121:5' Untranslated Regions; D001324:Autoantigens; D012333:RNA, Messenger; D012261:Ribonucleoproteins; D000097585:SS-B Antigen