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J. Biol. Chem., Vol. 281, Issue 16, 11115-11125, April 21, 2006

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Asymmetric Arginine Dimethylation of Heterogeneous Nuclear Ribonucleoprotein K by Protein-arginine Methyltransferase 1 Inhibits Its Interaction with c-Src^*

Antje Ostareck-Lederer¹, Dirk H. Ostareck, Karl P. Rucknagel, Angelika Schierhorn, Bodo Moritz, Stefan Huttelmaier^¶, Nadine Flach, Lusy Handoko^||, and Elmar Wahle²

From the Institute of Biochemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Strasse 3, 06120 Halle (Saale), the Max Planck Research Unit for Enzymology of Protein Folding, Weinbergweg 22, 06120 Halle (Saale), ^¶ZAMED, Martin-Luther-University Halle-Wittenberg, Heinrich Damerow Strasse 1, 06120 Halle (Saale), and the ^||Institute of Biochemistry, Biocenter at the University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany

Arginine methylation is a post-translational modification found in many RNA-binding proteins. Heterogeneous nuclear ribonucleoprotein K (hnRNP K) from HeLa cells was shown, by mass spectrometry and Edman degradation, to contain asymmetric N^G,N^G-dimethylarginine at five positions in its amino acid sequence (Arg²⁵⁶, Arg²⁵⁸, Arg²⁶⁸, Arg²⁹⁶, and Arg²⁹⁹). Whereas these five residues were quantitatively modified, Arg³⁰³ was asymmetrically dimethylated in <33% of hnRNP K and Arg²⁸⁷ was monomethylated in <10% of the protein. All other arginine residues were unmethylated. Protein-arginine methyltransferase 1 was identified as the only enzyme methylating hnRNP K in vitro and in vivo. An hnRNP K variant in which the five quantitatively modified arginine residues had been substituted was not methylated. Methylation of arginine residues by protein-arginine methyltransferase 1 did not influence the RNA-binding activity, the translation inhibitory function, or the cellular localization of hnRNP K but reduced the interaction of hnRNP K with the tyrosine kinase c-Src. This led to an inhibition of c-Src activation and hnRNP K phosphorylation. These findings support the role of arginine methylation in the regulation of protein-protein interactions.

Received for publication, December 7, 2005 , and in revised form, February 2, 2006.

^* This work was supported in part by a Heisenberg fellowship of the Deutsche Forschungsgemeinschaft (DFG) (to A. O.-L.) and by the DFG (Grants Os 290/2-1 to A. O.-L., Os 135/2-1,2 to D. H. O. and Grant SFB 610 to E. W.). 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 text, Ref. 1, and Fig. S1.

² Supported by the Fonds der Chemischen Industrie.

¹ To whom correspondence should be addressed. Tel.: 49-(0)345-552-4949; Fax: 49-(0)345-552-7014; E-mail: aostareck{at}biochemtech.uni-halle.de.

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