Rapsyn-acetylcholine receptor interactions: structural models inform mechanisms of clustering at the neuromuscular...

Synaptic communication across the neuromuscular junction is mediated by high-density clusters of the nicotinic acetylcholine receptor (nAChR), with the initiation and maintenance of clustering facilitated by a peripheral membrane protein, rapsyn. Despite the importance of both the nAChR and rapsyn to neuromuscular junction formation and function, structural insight into the rapsyn-nAChR complex and thus how the formation of this complex facilitates clustering is still lacking. In this review, we update our current understanding of nAChR-rapsyn interactions in the context of new structures of the muscle-type nAChR, as well as computationally predicted models of both rapsyn and the nAChR-rapsyn complex. By integrating domain-function studies, biochemical data, and both new and predicted structural data, we present a plausible model of nAChR-rapsyn complex that provides a framework for understanding both clustering at the neuromuscular junction and how mutations in rapsyn lead to the neuromuscular disease, congenital myasthenic syndrome.