title: Synergic interplay of the La motif, RRM1 and the interdomain linker of LARP6 in the recognition of collagen mRNA expands the RNA binding repertoire of the La module.
abstract: The La-related proteins (LARPs) form a diverse group of RNA-binding proteins characterized by the possession of a composite RNA binding unit, the La module. The La module comprises two domains, the La motif (LaM) and the RRM1, which together recognize and bind to a wide array of RNA substrates. Structural information regarding the La module is at present restricted to the prototypic La protein, which acts as an RNA chaperone binding to 3' UUUOH sequences of nascent RNA polymerase III transcripts. In contrast, LARP6 is implicated in the regulation of collagen synthesis and interacts with a specific stem-loop within the 5' UTR of the collagen mRNA. Here, we present the structure of the LaM and RRM1 of human LARP6 uncovering in both cases considerable structural variation in comparison to the equivalent domains in La and revealing an unprecedented fold for the RRM1. A mutagenic study guided by the structures revealed that RNA recognition requires synergy between the LaM and RRM1 as well as the participation of the interdomain linker, probably in realizing tandem domain configurations and dynamics required for substrate selectivity. Our study highlights a considerable complexity and plasticity in the architecture of the La module within LARPs.
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
authors.forename: Luigi
authors.initials: L
authors.lastname: Martino
authors.affiliation: Division of Molecular Structure, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Pennell
authors.affiliation: MRC Biomedical NMR Centre, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Geoff
authors.initials: G
authors.lastname: Kelly
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK Department of Biology, École Normale Supérieure de Lyon, CEDEX 07, France.
authors.forename: Baptiste
authors.initials: B
authors.lastname: Busi
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Brown
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
authors.forename: R Andrew
authors.initials: RA
authors.lastname: Atkinson
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
authors.forename: Nicholas J H
authors.initials: NJ
authors.lastname: Salisbury
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK Department of Biological Sciences, National University of Singapore, Singapore 117543.
authors.forename: Zi-Hao
authors.initials: ZH
authors.lastname: Ooi
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK Department of Biological Sciences, National University of Singapore, Singapore 117543.
authors.forename: Kang-Wei
authors.initials: KW
authors.lastname: See
authors.affiliation: Division of Molecular Structure, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Smerdon
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
authors.forename: Caterina
authors.initials: C
authors.lastname: Alfano
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
authors.forename: Tam T T
authors.initials: TT
authors.lastname: Bui
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK sasi.conte@kcl.ac.uk.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Conte
mesh_terms: D020121:5' Untranslated Regions; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001324:Autoantigens / Q000737:chemistry* / Q000235:genetics; D003094:Collagen / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D012261:Ribonucleoproteins / Q000737:chemistry* / Q000235:genetics; D016415:Sequence Alignment; D000097585:SS-B Antigen
chemical_list: D020121:5' Untranslated Regions; D001324:Autoantigens; D003094:Collagen; D012261:Ribonucleoproteins; D000097585:SS-B Antigen