title: La-related protein 1 (LARP1) binds the mRNA cap, blocking eIF4F assembly on TOP mRNAs.
abstract: The 5'terminal oligopyrimidine (5'TOP) motif is acis-regulatory RNA element located immediately downstream of the 7-methylguanosine [m7G] cap of TOP mRNAs, which encode ribosomal proteins and translation factors. In eukaryotes, this motif coordinates the synchronous and stoichiometric expression of the protein components of the translation machinery. La-related protein 1 (LARP1) binds TOP mRNAs, regulating their stability and translation. We present crystal structures of the human LARP1 DM15 region in complex with a 5'TOP motif, a cap analog (m7GTP), and a capped cytidine (m7GpppC), resolved to 2.6, 1.8 and 1.7 Å, respectively. Our binding, competition, and immunoprecipitation data corroborate and elaborate on the mechanism of 5'TOP motif binding by LARP1. We show that LARP1 directly binds the cap and adjacent 5'TOP motif of TOP mRNAs, effectively impeding access of eIF4E to the cap and preventing eIF4F assembly. Thus, LARP1 is a specialized TOP mRNA cap-binding protein that controls ribosome biogenesis.
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, United States.
authors.forename: Roni M
authors.identifier: 0000-0002-7469-4565
authors.initials: RM
authors.lastname: Lahr
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada.
authors.forename: Bruno D
authors.initials: BD
authors.lastname: Fonseca
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, United States.
authors.forename: Gabrielle E
authors.initials: GE
authors.lastname: Ciotti
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, United States.
authors.forename: Hiba A
authors.initials: HA
authors.lastname: Al-Ashtal
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Jia
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada.
authors.forename: Marius R
authors.initials: MR
authors.lastname: Niklaus
authors.affiliation: Department of Oncology, University of Oxford, Oxford, United Kingdom.
authors.forename: Sarah P
authors.initials: SP
authors.lastname: Blagden
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada.
authors.forename: Tommy
authors.initials: T
authors.lastname: Alain
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, United States.
authors.forename: Andrea J
authors.identifier: 0000-0003-1217-7412
authors.initials: AJ
authors.lastname: Berman
mesh_terms: D001324:Autoantigens / Q000737:chemistry* / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D018360:Crystallography, X-Ray; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors*; D039562:Eukaryotic Initiation Factor-4F / Q000037:antagonists & inhibitors*; D005786:Gene Expression Regulation; D008958:Models, Molecular; D011485:Protein Binding; D014176:Protein Biosynthesis; D011487:Protein Conformation; D038641:RNA 5' Terminal Oligopyrimidine Sequence; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D012261:Ribonucleoproteins / Q000737:chemistry* / Q000378:metabolism*; D000097585:SS-B Antigen
chemical_list: D001324:Autoantigens; D039561:Eukaryotic Initiation Factor-4E; D039562:Eukaryotic Initiation Factor-4F; D012333:RNA, Messenger; D012261:Ribonucleoproteins; D000097585:SS-B Antigen
keywords: 5' cap; E. coli; La-related protein 1; RNA binding protein; TOP mRNAs; X-ray crystallography; biochemistry; biophysics; eIF4E; human; structural biology