Human Molecular Genetics Advance Access published online on October 21, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg350
© 2003 by Oxford University Press
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1 Dept. of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322; Dept. of Cell and Structural Biology, University of Illinois, Urbana, IL 61801
* To whom correspondence should be addressed. E-mail: swarren{at}emory.edu.
Fragile X mental retardation protein, FMRP, is absent in patients with fragile X syndrome, a common form of mental retardation. FMRP is a nucleocytoplasmic RNA binding protein that is primarily associated with polyribosomes. FMRP is believed to be a translational repressor and may regulate the translation of certain mRNAs at the base of dendritic spines in neurons. However, little is known about the regulation of FMRP. Using mass spectrometry and site-directed mutagenesis, we show that FMRP is phosphorylated between residues 483 and 521, N-terminal to the RGG box, in both murine brain and in cultured cells. Primary phosphorylation occurs on the highly conserved serine 499, which triggers hierarchical phosphorylation of nearby serines. FMRP is phosphorylated within two to four hours of synthesis, however, phosphorylation has no effect on the half-life of the protein. In contrast to the Drosophila ortholog dFxr, the phosphorylation status of mammalian FMRP does not influence its association with specific mRNAs in vivo. However, we find unphosphorylated FMRP associated with actively translating polyribosomes while a fraction of phosphorylated FMRP is associated with apparently stalled polyribosomes. Our data suggest that the phosphorylation may regulate FMRP and that the release of FMRP-induced translational suppression may involve a dephosphorylation signal.
Article
Phosphorylation influences the translation state of FMRP-associated polyribosomes
2 Dept. of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322
3 Microchemical Facility, Emory University School of Medicine, Atlanta, GA 30322
4 Room 305E Whitehead Building, Dept. of Human Genetics, Emory University School of Medicine, 615 Michael St., Atlanta, GA 30322
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