MuSK is required for anchoring acetylcholinesterase at the neuromuscular junction

Abstract

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.

MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4

“…As such, antibodies that inhibit MuSK function would be expected to disrupt the architecture of the neuromuscular synapse as well as perturb neurotransmitter release and reception (9,18,19,34,(41)(42)(43)(44). Because the synaptic accumulation of acetylcholinesterase (AChE), like all other postsynaptic proteins, depends on MuSK (10,42), IgG4 antibodies to MuSK are likely to lower AChE expression at the synapse, which may explain the hypersensitivity of MuSK MG patients to AChE inhibitors.…”

Congenital Myasthenic Syndromes - Molecular Bases of Congenital Defects of Proteins at the Neuromuscular Junction

“…First, the collagen domain harbors two heparan sulfate proteoglycan (HSPG) binding domains (Deprez et al, 2003) that bind to HSPG, such as perlecan (Peng et al, 1999). Second, the C-terminal domain binds to MuSK (Cartaud et al, 2004).…”

Assembly and regulation of acetylcholinesterase at the vertebrate neuromuscular junction

“…Another possible ColQ-protein interaction has been described by Cartaud and colleagues [17] who suggested that the putative agrin receptor MuSK is also a receptor for ColQ-AChE and was required for AChE binding to the neuromuscular junction. Using a ColQ-GFP fusion protein expression to emulate expression of ColQ-AChE, and co-transfection with MuSK, the authors demonstrate that the surface clusters of ColQ-GFP co-distribute with endogenous perlecan and exogenous MuSK in COS-7 cells.…”