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: Thomas Maurin, Mireille Melko, Sabiha Abekhoukh, Olfa Khalfallah, Laetitia Davidovic, Marielle Jarjat, Simona D'Antoni, Maria Vincenza Catania, Hervé Moine, Elias Bechara, Barbara Bardoni
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 43 Issue 17 Pg. 8540-50 (Sep 30 2015) ISSN: 1362-4962 [Electronic] England
• PMID: 26250109 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Chemical References

• Fmr1 protein, mouse
• RNA, Messenger
• Fragile X Mental Retardation Protein
• G-Protein-Coupled Receptor Kinase 4
• GRK4 protein, human
• GRK4 protein, mouse

Topics

• Animals
• Binding Sites
• Cerebellum (metabolism)
• Fragile X Mental Retardation Protein (chemistry, genetics, metabolism)
• G-Protein-Coupled Receptor Kinase 4 (genetics, metabolism)
• Humans
• Mice
• Mice, Knockout
• Protein Binding
• Protein Biosynthesis
• Protein Interaction Domains and Motifs
• RNA, Messenger (chemistry, metabolism)