Human Molecular Genetics Advance Access originally published online on July 28, 2008
Human Molecular Genetics 2008 17(20):3236-3246; doi:10.1093/hmg/ddn219
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Tdrd3 is a novel stress granule-associated protein interacting with the Fragile-X syndrome protein FMRP
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1 Department of Biochemistry, Theodor Boveri Institute, Am Hubland, D-97074 Würzburg, Germany 2 Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany 3 Institute for Biology, University of Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany
* To whom correspondence should be addressed. Tel: +49 9318884029; Fax: +49 9318884028; Email: utz.fischer{at}biozentrum.uni-wuerzburg.de
Received April 16, 2008; Revised July 4, 2008; Accepted July 24, 2008
Tudor domains are widespread among proteins involved in RNA metabolism, but only in a few cases their cellular function has been analyzed in detail. Here, we report on the characterization of the ubiquitously expressed Tudor domain containing protein Tdrd3. Apart from its Tudor domain, we show that Tdrd3 possesses an oligosaccharide/nucleotide binding fold (OB-fold) and an ubiquitin associated domain capable of binding tetra-ubiquitin. A set of biochemical experiments revealed an interaction of Tdrd3 with FMRP, the product of the gene affected in Fragile X syndrome, and its autosomal homologs FXR1 and FXR2. FMRP has been implicated in the translational regulation of target mRNAs and shown to be a component of stress granules (SG). We demonstrate that overexpression of Tdrd3 in cells induces the formation of SGs and as a result leads to its co-localization with endogenous FMRP in these structures. Interestingly, the disease-associated FMRP missense mutation I304N identified in a Fragile X patient severely impairs the interaction with Tdrd3 in biochemical experiments. We propose a contribution of Tdrd3 to FMRP-mediated translational repression and suggest that the loss of the FMRP–Tdrd3 interaction caused by the I304N mutation might contribute to the pathogenesis of Fragile X syndrome.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors. Sequence information has been submitted to GenBank with the accession number EU643838.
Present address: Roche Diagnostics GmbH, Nonnenwald 2, D-82377 Penzberg, Germany.
Present address: TRION Pharma GmbH, Frankfurter Ring 193a, D-80807 München, Germany.
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