MAGI-1c: A synaptic MAGUK interacting with MuSK at the vertebrate neuromuscular junction

The muscle-specific receptor tyrosine kinase (MuSK) forms part of a recepto r complex. activated by nerve-derived agrin, that orchestrates the differen tiation of the neuromuscular junction (NMJ). The molecular events linking M uSK activation with postsynaptic differentiation are not fully understood. In an attempt to identify partners and/or effecters of MuSK, cross-linking and immunopurification experiments were performed in purified postsynaptic membranes from the Torpedo electrocyte. a model system for the NMJ. Matrix- assisted laser desorption ionization-time of flight (MALDI-TOF) analysis wa s conducted on both cross-link products, and on the major peptide coimmunop urified with MuSK; this analysis identified a polypeptide corresponding to the COOH-terminal fragment of membrane-associated guanylate kinase (MAGUK) with inverted domain organization (MAGI)-1c. A bona fide MAGI-1c (150 kD) w as detected by Western blotting in the postsynaptic membrane of Torpedo ele ctrocytes, and in a high molecular mass cross-link prod net of MuSK. Immuno fluorescence experiments showed that MAGI-1c is localized specifically at t he adult rat NMJ, but is absent from agrin-induced acetylcholine receptor c lusters in myotubes in vitro. In the central nervous system, MAGUKs play a primary role as scaffolding proteins that organize cytoskeletal signaling c omplexes at excitatory synapses. Our data suggest that a protein from the M AGUK family is involved in the MuSK signaling pathway at the vertebrate NMJ .