Fragile X syndrome (FXS) is the most common form of inherited mental impairement, causing a range of intellectual disabilities. This disorder is caused by a CGG trinucleotide overexpansion within the fragile X mental retardation (<i>FMR1</i>) gene, leading to hypermethylation of the promoter region and subsequent transcriptional silencing of the fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein involved in mRNA translation and nucleocytoplasmic shuttling. The full-length protein contains multiple RNA-binding domains, including two K-homology (KH) domains, as well as an arginine-glycine-glycine box (RGG box). The RGG box, has been shown to specifically target G-quadruplex secondary structures within RNA. G-quadruplexes are three-dimensional structures formed by two or more stacks of Hoogsteen hydrogen-bonded G-quartets within guanine-rich nucleic acids and are stabilized by K<sup>+</sup> ions. Here, we hypothesized the formation of a G-quadruplex secondary structure within a guanine-rich region of the mRNA encoding for the heterogenous nuclear ribonucleoprotein K (hnRNP K), an RNA-binding protein relevant in many neurological diseases. Using various biophysical techniques, such as NMR spectroscopy, CD spectroscopy, and UV thermal denaturation experiments, we have characterized a G-quadruplex structure within hnRNP K mRNA. Furthermore, we have demonstrated through electrophoretic mobility shift assays that this G-quadruplex structure is recognized by the RGG box of FMRP, implicating a potential molecular pathway which could be targeted for therapeutic intervention in diseases related to the translational downregulation of hnRNP K.

Investigation of heterogeneous nuclear ribonucleoprotein K mRNA and its interactions with the fragile X mental retardation protein

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.