title: The FMRP/GRK4 mRNA interaction uncovers a new mode of binding of the Fragile X mental retardation protein in cerebellum.
abstract: Fragile X syndrome (FXS), the most common form of inherited intellectual disability, is caused by the silencing of the FMR1 gene encoding an RNA-binding protein (FMRP) mainly involved in translational control. We characterized the interaction between FMRP and the mRNA of GRK4, a member of the guanine nucleotide-binding protein (G protein)-coupled receptor kinase super-family, both in vitro and in vivo. While the mRNA level of GRK4 is unchanged in the absence or in the presence of FMRP in different regions of the brain, GRK4 protein level is increased in Fmr1-null cerebellum, suggesting that FMRP negatively modulates the expression of GRK4 at the translational level in this brain region. The C-terminal region of FMRP interacts with a domain of GRK4 mRNA, that we called G4RIF, that is folded in four stem loops. The SL1 stem loop of G4RIF is protected by FMRP and is part of the S1/S2 sub-domain that directs translation repression of a reporter mRNA by FMRP. These data confirm the role of the G4RIF/FMRP complex in translational regulation. Considering the role of GRK4 in GABAB receptors desensitization, our results suggest that an increased GRK4 levels in FXS might contribute to cerebellum-dependent phenotypes through a deregulated desensitization of GABAB receptors.
authors.affiliation: CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, 06560 Valbonne Sophia-Antipolis, France University of Nice Sophia-Antipolis, 06103 Nice, FRANCE CNRS LIA 'Neogenex', 06560 Valbonne Sophia-Antipolis, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Maurin
authors.affiliation: CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, 06560 Valbonne Sophia-Antipolis, France University of Nice Sophia-Antipolis, 06103 Nice, FRANCE CNRS LIA 'Neogenex', 06560 Valbonne Sophia-Antipolis, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Melko
authors.affiliation: CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, 06560 Valbonne Sophia-Antipolis, France University of Nice Sophia-Antipolis, 06103 Nice, FRANCE CNRS LIA 'Neogenex', 06560 Valbonne Sophia-Antipolis, France.
authors.forename: Sabiha
authors.initials: S
authors.lastname: Abekhoukh
authors.affiliation: CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, 06560 Valbonne Sophia-Antipolis, France University of Nice Sophia-Antipolis, 06103 Nice, FRANCE CNRS LIA 'Neogenex', 06560 Valbonne Sophia-Antipolis, France.
authors.forename: Olfa
authors.initials: O
authors.lastname: Khalfallah
authors.affiliation: CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, 06560 Valbonne Sophia-Antipolis, France University of Nice Sophia-Antipolis, 06103 Nice, FRANCE CNRS LIA 'Neogenex', 06560 Valbonne Sophia-Antipolis, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Davidovic
authors.affiliation: CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, 06560 Valbonne Sophia-Antipolis, France University of Nice Sophia-Antipolis, 06103 Nice, FRANCE CNRS LIA 'Neogenex', 06560 Valbonne Sophia-Antipolis, France.
authors.forename: Marielle
authors.initials: M
authors.lastname: Jarjat
authors.affiliation: Institute of Neurological Sciences, The National Research Council of Italy, 95126 Catania, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: D'Antoni
authors.affiliation: Institute of Neurological Sciences, The National Research Council of Italy, 95126 Catania, Italy IRCCS Oasi Maria SS, 94018 Troina (EN), Italy.
authors.forename: Maria Vincenza
authors.initials: MV
authors.lastname: Catania
authors.affiliation: IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), CNRS, UMR7104, Inserm U596, Collège de France, Strasbourg University, 67400 Illkirch-Graffenstaden, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Moine
authors.affiliation: CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, 06560 Valbonne Sophia-Antipolis, France University of Nice Sophia-Antipolis, 06103 Nice, FRANCE CNRS LIA 'Neogenex', 06560 Valbonne Sophia-Antipolis, France.
authors.forename: Elias
authors.initials: E
authors.lastname: Bechara
authors.affiliation: CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, 06560 Valbonne Sophia-Antipolis, France University of Nice Sophia-Antipolis, 06103 Nice, FRANCE CNRS LIA 'Neogenex', 06560 Valbonne Sophia-Antipolis, France bardoni@ipmc.cnrs.fr.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bardoni
mesh_terms: D000818:Animals; D001665:Binding Sites; D002531:Cerebellum / Q000378:metabolism*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054771:G-Protein-Coupled Receptor Kinase 4 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D014176:Protein Biosynthesis; D054730:Protein Interaction Domains and Motifs; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D054771:G-Protein-Coupled Receptor Kinase 4; D012333:RNA, Messenger; C497684:Fmr1 protein, mouse; C517855:GRK4 protein, human; C517853:GRK4 protein, mouse