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First published online April 24, 2006
doi: 10.1242/10.1242/jcs.02882

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Methylation regulates the intracellular protein-protein and protein-RNA interactions of FMRP

¹ Biochemical Molecular Neurobiology Laboratory, Department of Molecular Biology, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA
² Tissue Culture Laboratory, Department of Pathological Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA
³ Department of Pharmacology and Toxicology, Center for Neuroscience, University at Buffalo School of Medicine State University of New York, 102 Farber Hall, Buffalo, NY 14214, USA

^* Author for correspondence (e-mail: rbdenman{at}yahoo.com)

Accepted 11 January 2006

FMRP, the fragile X mental retardation protein, is an RNA-binding protein that interacts with 4% of fetal brain mRNA. We have recently shown that a methyltransferase (MT) co-translationally methylates FMRP in vitro and that methylation modulates the ability of FMRP to bind mRNA. Here, we recapitulate these in vitro data in vivo, demonstrating that methylation of FMRP affects its ability to bind to FXR1P and regulate the translation of FMRP target mRNAs. Additionally, using double-label fluorescence confocal microscopy, we identified a subpopulation of FMRP-containing small cytoplasmic granules that are distinguishable from larger stress granules. Using the oxidative-stress induced accumulation of abortive pre-initiation complexes as a measure of the association of FMRP with translational components, we have demonstrated that FMRP associates with ribosomes during initiation and, more importantly, that methylation regulates this process by influencing the ratio of FMRP-homodimer-containing mRNPs to FMRP-FXR1P-heterodimer-containing mRNPs. These data suggest a vital role for methylation in normal FMRP functioning.

Key words: Fragile X syndrome, FMRP, Methylation, PRMT, Stress granules, Cytoplasmic granules

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