<i>FMR1</i> Protein: Conserved RNP Family Domains and Selective RNA Binding

TLDR

Fragile X syndrome results from transcriptional silencing of FMR1 due to a trinucleotide repeat expansion, and the normal role of its protein product, FMRP, in RNA binding and neuronal function remains unclear, potentially explaining the disorder’s pleiotropic phenotype. The study identified RNP domains in FMRP that support two stoichiometric RNA binding sites, with FMRP binding its own mRNA at 5.7 nM affinity and interacting with roughly 4 % of human fetal brain transcripts.

Abstract

Fragile X syndrome is the result of transcriptional suppression of the gene FMR1 as a result of a trinucleotide repeat expansion mutation. The normal function of the FMR1 protein (FMRP) and the mechanism by which its absence leads to mental retardation are unknown. Ribonucleoprotein particle (RNP) domains were identified within FMRP, and RNA was shown to bind in stoichiometric ratios, which suggests that there are two RNA binding sites per FMRP molecule. FMRP was able to bind to its own message with high affinity (dissociation constant = 5.7 nM) and interacted with approximately 4 percent of human fetal brain messages. The absence of the normal interaction of FMRP with a subset of RNA molecules might result in the pleiotropic phenotype associated with fragile X syndrome.