G-quartet-dependent recognition between the FMRP RGG box and RNA

Abstract

Fragile-X syndrome, the most common monogenic form of mental retardation, is caused by down-regulation of the expression of Fragile X Mental Retardation Protein (FMRP). FMRP is a multifunctional, multidomain RNA-binding protein that acts as a translational repressor in neuronal cells. Interaction between FMRP and mRNA targets involves an RGG box, a protein motif commonly thought to mediate unspecific interactions with nucleic acids. Instead, FMRP RGG box has been shown to recognize RNA G-quartet structures specifically and to be necessary in neurons for RNP particle formation and dendritic mRNA localization. In the present study, we have characterized structurally three representative RNA targets of FMRP in their unbound form and in complex with the RGG box. We observe a large heterogeneity in the conformation of the RNA targets and in their RGG binding mode, which could be the basis of recognition specificity. We also found that G-quartet formation occurs not only intramolecularly but can also be mediated by RNA dimerization. These findings suggest a potential role of RNA:RNA interactions in protein:RNA complexes and in RNP particle assembly.