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J. Biol. Chem., Vol. 281, Issue 48, 36835-36845, December 1, 2006

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Activation of Muscle-specific Receptor Tyrosine Kinase and Binding to Dystroglycan Are Regulated by Alternative mRNA Splicing of Agrin^*

Patrick Scotton, Dorothee Bleckmann, Michael Stebler, Francesca Sciandra^¶, Andrea Brancaccio^¶, Thomas Meier, Jörg Stetefeld¹, and Markus A. Ruegg²

From the Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland, Santhera Pharmaceuticals (Switzerland) Ltd., Hammerstrasse 47, CH-4410 Liestal, Switzerland, and the ^¶Istituto di Chimica del Riconoscimento Molecolare (CNR), c/o Istituto di Biochimica e Biochimica Clinica, Università Cattolica del Sacro Cuore, Largo Francesco Vito n.1, 00168 Rome, Italy

Agrin induces the aggregation of postsynaptic proteins at the neuromuscular junction (NMJ). This activity requires the receptor-tyrosine kinase MuSK. Agrin isoforms differ in short amino acid stretches at two sites, called A and B, that are localized in the two most C-terminal laminin G (LG) domains. Importantly, agrin isoforms greatly differ in their activities of inducing MuSK phosphorylation and of binding to -dystroglycan. By using site-directed mutagenesis, we characterized the amino acids important for these activities of agrin. We find that the conserved tripeptide asparagineglutamate-isoleucine in the eight-amino acid long insert at the B-site is necessary and sufficient for full MuSK phosphorylation activity. However, even if all eight amino acids were replaced by alanines, this agrin mutant still has significantly higher MuSK phosphorylation activity than the splice version lacking any insert. We also show that binding to -dystroglycan requires at least two LG domains and that amino acid inserts at the A and the B splice sites negatively affect binding.

Received for publication, August 17, 2006 , and in revised form, September 22, 2006.

^* This work was supported in part by grants from the Commission for Technology and Innovation (CTI), the Swiss National Science Foundation, the Swiss Foundation for Research on Muscle Diseases, the Canton Basel-Stadt. Work was also supported by the Italian Telethon (to A. B.). 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. S1 and S2.

¹ To whom correspondence may be addressed: Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland. Tel.: 41-61-267-20-91; Fax: 41-61-267-21-09; E-mail: joerg.stetefeld{at}unibas.ch. ² To whom correspondence may be addressed: Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland. Tel.: 41-61-267-22-23; Fax: 41-61-267-22-08; E-mail: markus-a.ruegg{at}unibas.ch.

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