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FMRP interacts with G-quadruplex structures in the 3’-UTR of its dendritic target Shank1 mRNA

ABSTRACT Fragile X syndrome (FXS), the most common cause of inherited intellectual disability, is caused by the loss of expression of the fragile X mental retardation protein (FMRP). FMRP, which regulates the transport and translation of specific mRNAs, uses its RGG box domain to bind mRNA targets that form G-quadruplex structures. One of the FMRP in vivo targets, Shank1 mRNA, encodes the master scaffold proteins of the postsynaptic density (PSD) which regulate the size and shape of dendritic spines because of their capacity to interact with many different PSD components. Due to their effect on spine morphology, altered translational regulation of Shank1 transcripts may contribute to the FXS pathology. We hypothesized that the FMRP interactions with Shank1 mRNA are mediated by the recognition of the G quadruplex structure, which has not been previously demonstrated. In this study we used biophysical techniques to analyze the Shank1 mRNA 3’-UTR and its interactions with FMRP and its phosphorylated mimic FMRP S500D. We found that the Shank1 mRNA 3 ′ -UTR adopts two very stable intramolecular G-quadruplexes which are bound specifically and with high affinity by FMRP both in vitro and in vivo. These results suggest a role of G-quadruplex RNA motif as a structural element in the common mechanism of FMRP regulation of its dendritic mRNA targets.