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J. Biol. Chem., Vol. 280, Issue 50, 41449-41457, December 16, 2005

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Conjugation of LG Domains of Agrins and Perlecan to Polymerizing Laminin-2 Promotes Acetylcholine Receptor Clustering^*

Sergei P. Smirnov, Patrizia Barzaghi, Karen K. McKee, Markus A. Ruegg, and Peter D. Yurchenco1

From the Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854 and Biozentrum, University of Basel, CH-4056 Basel, Switzerland

Neuromuscular junction (NMJ) assembly is characterized by the clustering and neuronal alignment of acetylcholine receptors (AChRs). In this study we have addressed post-synaptic contributions to assembly that may arise from the NMJ basement membrane with cultured myotubes. We show that the cell surface-binding LG domains of non-neural (muscle) agrin and perlecan promote AChR clustering in the presence of laminin-2. This type of AChR clustering occurs with a several hour lag, requires muscle-specific kinase (MuSK), and is accompanied by tyrosine phosphorylation of MuSK and AChR. It also requires conjugation of the agrin or perlecan to laminin together with laminin polymerization. Furthermore, AChR clustering can be mimicked with antibody binding to non-neural agrin, supporting a mechanism of ligand aggregation. Neural agrin, in addition to its unique ability to cluster AChRs through its B/z sequence insert, also exhibits laminin-dependent AChR clustering, the latter enhancing and stabilizing its activity. Finally, we show that type IV collagen, which lacks clustering activity on its own, stabilizes laminin-dependent AChR clusters. These findings provide evidence for cooperative and partially redundant MuSK-dependent functions of basement membrane in AChR assembly that can enhance neural agrin activity yet operate in its absence. Such interactions may contribute to the assembly of aneural AChR clusters that precede neural agrin release as well as affect later NMJ development.

Received for publication, August 12, 2005 , and in revised form, September 21, 2005.

^* This work was supported by National Institutes of Health Grant R01-NS38469 (to P. D. Y.) and grants from the Swiss National Science Foundation, the Muscular Dystrophy Association U.S.A, and the Swiss Foundation for Research on Muscle Diseases (to M. A. R.). 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 should be addressed: 675 Hoes Lane, Piscataway, NJ 08854. Tel.: 732-235-5166; Fax: 732-235-4825; E-mail: yurchenc{at}umdnj.edu.

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