Abstract
The tandem Agenet domain (TAD) of fragile X mental retardation protein (FMRP) protein is considered to be a member of the methyl-lysine-binding Tudor domain “Royal family”. Several groups have reported that the TAD binds with methylated histones and plays a role in DNA damage responses. FMRP is a RNA-binding protein predominantly resident in cytoplasm. Therefore, in this study, we identified DDX5, FUS, EWSR1 and LSM14A as TAD-interacting proteins sensitive to F32L and/or Y96L mutation by pull-down assays and mass spectrometry. We also showed that the interaction is potentially mediated by RGG/RG motifs. Furthermore, when FMRP was knocked-down, translocation of exogenously expressed wild-type FUS and disease-related mutant R514G was observed. This study may provide a novel insight into FMRP involvement in the intracellular localization of FUS and pathology of FUS-related amyotrophic lateral sclerosis.
Highlights
Silencing or mutation of the human FMR1 gene underlies the molecular mechanism of fragile X syndrome (FXS)[1, 2]
Its putative methyl-binding pocket mutants F32L and Y96L bound FXR1, Flag-PLK1 and Flag-BAIAP2L1 with similar affinity compared with the wild-type, which suggests the mutations do not inactivate all functions of fragile X mental retardation protein (FMRP)-1-200
LSM14A, EWSR1, DDX5 and FUS were sensitive to the mutations, indicating that their interaction with tandem Agenet domain (TAD) is potentially mediated by protein methylation
Summary
Silencing or mutation of the human FMR1 gene underlies the molecular mechanism of fragile X syndrome (FXS)[1, 2]. In 2014, Alpatov et al showed that the TAD of FMRP binds to mono-nucleosomes in vitro in an interaction that is mediated by the methylated lysines in the histone H313. We report that the TADs of FMRP bind to the protein FUS via an interaction that is potentially mediated by the RGG/RG motifs.
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