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Human Molecular Genetics Advance Access originally published online on October 21, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 24 3295-3305
DOI: 10.1093/hmg/ddg350
© 2003 Oxford University Press

Phosphorylation influences the translation state of FMRP-associated polyribosomes

Stephanie Ceman1,{dagger},{ddagger}, William T. O'Donnell1,{dagger}, Matt Reed2, Stephana Patton1, Jan Pohl2 and Stephen T. Warren1,*

1Department of Human Genetics and 2Microchemical Facility, Emory University School of Medicine, Atlanta, GA 30322, USA

Received July 28, 2003; Accepted October 6, 2003

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, both in 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 2–4 h 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.

* To whom correspondence should be addressed at: Room 305E Whitehead Building, Department of Human Genetics, 615 Michael St, Atlanta, GA 30322, USA. Tel: +1 4047275979; Fax: +1 4047273949; E-mail: swarren{at}emory.edu

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.

{ddagger} Present address:

Department of Cell and Structural Biology, University of Illinois, Urbana, IL 61801, USA.


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