Résumé :
|
Communication n° 647 In cholinergic synapses, the level of Acetycholine (ACh) is controlled in space and time by Acetylcholinesterase (AChE). At neuromuscular junctions, the enzyme is mostly accumulated in the synaptic basal lamina by a specific collagen called ColQ. The mutations identified in human or the absence of ColQ in mutant mice are characterized by a deficiency in AChE which leads to a myasthenic syndrome in patients. What are the mechanisms of the hetero-oligomer AChE/ColQ accumulation? Previous studies have shown that part of this process relies on ColQ interaction with a heparan sulfate proteoglycan through the 2 heparin-binding sites contained in ColQ. ColQ has indeed been shown to interact with Perlecan which itself binds to Dystroglycan (Peng et al., 1999; Jacobson et al., 2001). Analysis of ColQ C-terminus mutations in myasthenic patients has revealed that an other partner is implicated in AChE accumulation. We have identified this partner as MuSK (Cartaud et al., 2004). MuSK is a receptor tyrosine kinase specifically expressed in muscle and a key player at the neuromuscular junction in the formation of postsynaptic densities. We show that the 2 heparin-binding sites and the C-terminus of ColQ are indispensable for AChE/ColQ accumulation. Domains of interaction between ColQ and MuSK will be discussed as well as the physiological implications of ColQ/MuSK interaction. Peng et al. (1999) JCB, 145, 911-921; Jacobson et al. (2001) JCB, 152, 435-450; Cartaud et al. (2004) JCB, 165, 505-515.
|