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Published 24 May 2004. doi:10.1083/jcb.200307164
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 165, Number 4, 505-515
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Article

 MuSK is required for anchoring acetylcholinesterase at the neuromuscular junction

Annie Cartaud1, Laure Strochlic1, Manuel Guerra2, Benoît Blanchard1, Monique Lambergeon2, Eric Krejci2, Jean Cartaud1, and Claire Legay2

1 Biologie Cellulaire des Membranes, Institut Jacques Monod, UMR 7592 Centre National de la Recherche Scientifique (CNRS), Universités Paris 6 and Paris 7, 75251 Paris, Cedex 05, France
2 Neurobiologie Moléculaire et Cellulaire, Ecole Normale Supérieure, UMR 8544 CNRS, 75230 Paris, Cedex 05, France

Address correspondence to Claire Legay, Laboratoire de neurobiologie Mol, 46 rue d'Ulm, 75230 Paris, Cedex 05, France. Tel.: 33-1-42-86-20-68. email: claire.legay{at}univ-paris5.fr

At the neuromuscular junction, acetylcholinesterase (AChE) is mainly present as asymmetric forms in which tetramers of catalytic subunits are associated to a specific collagen, collagen Q (ColQ). The accumulation of the enzyme in the synaptic basal lamina strictly relies on ColQ. This has been shown to be mediated by interaction between ColQ and perlecan, which itself binds dystroglycan. Here, using transfected mutants of ColQ in a ColQ-deficient muscle cell line or COS-7 cells, we report that ColQ clusterizes through a more complex mechanism. This process requires two heparin-binding sites contained in the collagen domain as well as the COOH terminus of ColQ. Cross-linking and immunoprecipitation experiments in Torpedo postsynaptic membranes together with transfection experiments with muscle-specific kinase (MuSK) constructs in MuSK-deficient myotubes or COS-7 cells provide the first evidence that ColQ binds MuSK. Together, our data suggest that a ternary complex containing ColQ, perlecan, and MuSK is required for AChE clustering and support the notion that MuSK dictates AChE synaptic localization at the neuromuscular junction.

Key Words: synapse; cholinergic transmission; perlecan; ColQ; heparin-binding sites

Abbreviations used in this paper: AChE, acetylcholinesterase; AChR, acetylcholine receptor; A form, asymmetric form; ColQ, collagen Q; HBS, heparin-binding sites; HSPG, heparan sulfate proteoglycan; MALDI-TOF, matrix-assisted laser desorption ionization-time of flight; MT, myotube; MuSK, muscle-specific kinase; NMJ, neuromuscular junction; PRAD, proline-rich domain; wt, wild-type.


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