Abstract
Fragile X syndrome, the most frequent form of inherited mental retardation, is due to the absence of Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein involved in several steps of RNA metabolism. To date, two RNA motifs have been found to mediate FMRP/RNA interaction, the G-quartet and the “kissing complex,” which both induce translational repression in the presence of FMRP. We show here a new role for FMRP as a positive modulator of translation. FMRP specifically binds Superoxide Dismutase 1 (Sod1) mRNA with high affinity through a novel RNA motif, SoSLIP (Sod1 mRNA Stem Loops Interacting with FMRP), which is folded as three independent stem-loop structures. FMRP induces a structural modification of the SoSLIP motif upon its interaction with it. SoSLIP also behaves as a translational activator whose action is potentiated by the interaction with FMRP. The absence of FMRP results in decreased expression of Sod1. Because it has been observed that brain metabolism of FMR1 null mice is more sensitive to oxidative stress, we propose that the deregulation of Sod1 expression may be at the basis of several traits of the physiopathology of the Fragile X syndrome, such as anxiety, sleep troubles, and autism.
Highlights
Fragile X Mental Retardation Protein (FMRP) is an RNAbinding protein whose absence causes the Fragile X syndrome, the most frequent form of inherited mental retardation [1]
Scientists studying Fragile X syndrome have focused on identifying the RNAs that are bound by FMRP
When FMRP binds these structures, the translation of the RNA into its protein product is inhibited. In this new study we have identified a third FMRP-binding RNA structure that is found in the mRNA that encodes superoxide dismutase, an oxidative-stress-mitigating enzyme
Summary
Fragile X Mental Retardation Protein (FMRP) is an RNAbinding protein whose absence causes the Fragile X syndrome, the most frequent form of inherited mental retardation [1]. An increasing body of evidence suggests that FMRP has a complex function, reflecting its involvement in the control of hundreds of mRNA targets via its different RNAbinding domains. The RGG box is able to bind G-quartet RNA with high affinity [3,4]. This structure is present in several FMRP mRNA targets, such as Fragile X Mental Retardation 1 (FMR1), Microtubules Associated Protein 1B (MAP1B), and PP2Ac Protein Phosphatase 2A catalytic subunit (PP2Ac) [3,4,5]. FMRP is able to shuttle between nucleus and cytoplasm, where it is mostly associated with polyribosomes, suggesting an implication in translational control [1]. After traveling along dendrites, FMRP associates with polyribosomes localized at the synapse to participate in the translational control of proteins synthesized in this compartment [8]
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