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J. Biol. Chem., Vol. 283, Issue 29, 20408-20420, July 18, 2008

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Promiscuous Modification of the Nuclear Poly(A)-binding Protein by Multiple Protein-arginine Methyltransferases Does Not Affect the Aggregation Behavior^*

Katharina Fronz, Silke Otto, Knut Kölbel, Uwe Kühn, Henning Friedrich, Angelika Schierhorn, Annette G. Beck-Sickinger, Antje Ostareck-Lederer, and Elmar Wahle¹

From the Institute of Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Strasse 3, 06120 Halle and Institute of Biochemistry, University of Leipzig, Brüderstrasse 34, 04103 Leipzig, Germany

The mammalian nuclear poly(A)-binding protein, PABPN1, carries 13 asymmetrically dimethylated arginine residues in its C-terminal domain. By fractionation of cell extracts, we found that protein-arginine methyltransferases (PRMTs)-1, -3, and -6 are responsible for the modification of PABPN1. Recombinant PRMT1, -3, and -6 also methylated PABPN1. Our data suggest that these enzymes act on their own, and additional polypeptides are not involved in recognizing PABPN1 as a substrate. PRMT1 is the predominant methyltransferase acting on PABPN1. Nevertheless, PABPN1 was almost fully methylated in a Prmt1^-/- cell line; thus, PRMT3 and -6 suffice for methylation. In contrast to PABPN1, the heterogeneous nuclear ribonucleoprotein (hnRNP) K is selectively methylated only by PRMT1. Efficient methylation of synthetic peptides derived from PABPN1 or hnRNP K suggested that PRMT1, -3, and -6 recognize their substrates by interacting with local amino acid sequences and not with additional domains of the substrates. However, the use of fusion proteins suggested that the inability of PRMT3 and -6 to modify hnRNP K is because of structural masking of the methyl-accepting amino acid sequences by neighboring domains. Mutations leading to intracellular aggregation of PABPN1 cause the disease oculopharyngeal muscular dystrophy. The C-terminal domain containing the methylated arginine residues is known to promote PAPBN1 self-association, and arginine methylation has been reported to inhibit self-association of an orthologous protein. Thus, arginine methylation might be relevant for oculopharyngeal muscular dystrophy. However, in two different types of assays we have been unable to detect any effect of arginine methylation on the aggregation of bovine PABPN1.

Received for publication, March 25, 2008 , and in revised form, May 7, 2008.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant SFB610 (to A. O.-L. and E. W.) and European Union Grant LSHM-CT-2005-018675 (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 Figs. 1-6, Table 1, and additional references.

This paper is dedicated to the memory of Henning Friedrich who passed away January 5, 2007. Henning contributed to studies of PABPN1 when he was an undergraduate student in our laboratory.

¹ To whom correspondence should be addressed. Tel.: 49-345-5524920; Fax: 49-345-5527014; E-mail: ewahle{at}biochemtech.uni-halle.de.

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