title: The structure of the N-terminal domain of the fragile X mental retardation protein: a platform for protein-protein interaction.
abstract: FMRP, whose lack of expression causes the X-linked fragile X syndrome, is a modular RNA binding protein thought to be involved in posttranslational regulation. We have solved the structure in solution of the N-terminal domain of FMRP (NDF), a functionally important region involved in multiple interactions. The structure consists of a composite fold comprising two repeats of a Tudor motif followed by a short alpha helix. The interactions between the three structural elements are essential for the stability of the NDF fold. Although structurally similar, the two repeats have different dynamic and functional properties. The second, more flexible repeat is responsible for interacting both with methylated lysine and with 82-FIP, one of the FMRP nuclear partners. NDF contains a 3D nucleolar localization signal, since destabilization of its fold leads to altered nucleolar localization of FMRP. We suggest that the NDF composite fold determines an allosteric mechanism that regulates the FMRP functions.
authors.affiliation: Molecular Structure Division, National Institute for Medical Research, London NW7 1AA, UK.
authors.forename: Andres
authors.initials: A
authors.lastname: Ramos
authors.forename: David
authors.initials: D
authors.lastname: Hollingworth
authors.forename: Salvatore
authors.initials: S
authors.lastname: Adinolfi
authors.forename: Marie
authors.initials: M
authors.lastname: Castets
authors.forename: Geoff
authors.initials: G
authors.lastname: Kelly
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Frenkiel
authors.forename: Barbara
authors.initials: B
authors.lastname: Bardoni
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pastore
mesh_terms: D000494:Allosteric Regulation / Q000502:physiology; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000378:metabolism; D018360:Crystallography, X-Ray; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D009687:Nuclear Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D017354:Point Mutation; D017510:Protein Folding; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins
chemical_list: D002352:Carrier Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D008239:Lysine; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D016601:RNA-Binding Proteins; C477652:NUFIP2 protein, human