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J. Biol. Chem., Vol. 280, Issue 35, 30888-30898, September 2, 2005

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Arginine Methylation of Yeast mRNA-binding Protein Npl3 Directly Affects Its Function, Nuclear Export, and Intranuclear Protein Interactions^*

Anne E. McBride, Jeffrey T. Cook, Elizabeth A. Stemmler, Kate L. Rutledge, Kelly A. McGrath, and Jeffrey A. Rubens

From the Departments of Biology and Chemistry, Bowdoin College, Brunswick, Maine 04011

Arginine methylation can affect both nucleocytoplasmic transport and protein-protein interactions of RNA-binding proteins. These effects are seen in cells that lack the yeast hnRNP methyltransferase (HMT1), raising the question of whether effects on specific proteins are direct or indirect. The presence of multiple arginines in individual methylated proteins also raises the question of whether overall methylation or methylation of a subset of arginines affects protein function. We have used the yeast mRNA-binding protein Npl3 to address these questions in vivo. Matrix-assisted laser desorption/ionization Fourier transform mass spectrometry was used to identify 17 methylated arginines in Npl3 purified from yeast: whereas 10 Arg-Gly-Gly (RGG) tripeptides were exclusively dimethylated, variable levels of methylation were found for 5 RGG and 2 RG motif arginines. We constructed a set of Npl3 proteins in which subsets of the RGG arginines were mutated to lysine. Expression of these mutant proteins as the sole form of Npl3 specifically affected growth of a strain that requires Hmt1. Although decreased growth generally correlated with increased numbers of Arg-to-Lys mutations, lysine substitutions in the N terminus of the RGG domain showed more severe effects. Npl3 with all 15 RGG arginines mutated to lysine exited the nucleus independent of Hmt1, indicating a direct effect of methylation on Npl3 transport. These mutations also resulted in a decreased, methylation-independent interaction of Npl3 with transcription elongation factor Tho2 and inhibited Npl3 self-association. These results support a model in which arginine methylation facilitates Npl3 export directly by weakening contacts with nuclear proteins.

Received for publication, May 27, 2005 , and in revised form, June 30, 2005.

^* This work was supported by Grants MCB-0235590 (to A. E. M.) and MRI-0116416 (to E. A. S.) from the National Science Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Data.

Supported in part by James Stacy Coles and American Society for Microbiology Undergraduate Research Fellowships.

To whom correspondence should be addressed: Dept. of Biology, 6500 College Station, Bowdoin College, Brunswick, ME 04011. Tel.: 207-798-7109; Fax: 207-725-3405; E-mail: amcbride{at}bowdoin.edu.

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