Neuron
Volume 92, Issue 5, 7 December 2016, Pages 1007-1019
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Article
Enzymatic Activity of the Scaffold Protein Rapsyn for Synapse Formation

https://doi.org/10.1016/j.neuron.2016.10.023Get rights and content
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Highlights

  • RING domain of rapsyn contains E3 ligase activity

  • Rapsyn E3 ligase activity catalyzes neddylation as well as ubiquitination

  • Agrin promotes AChR neddylation for cluster formation

  • Rapsyn E3 ligase activity is required for AChR clustering and NMJ assembly

Summary

Neurotransmission is ensured by a high concentration of neurotransmitter receptors at the postsynaptic membrane. This is mediated by scaffold proteins that bridge the receptors with cytoskeleton. One such protein is rapsyn (receptor-associated protein at synapse), which is essential for acetylcholine receptor (AChR) clustering and NMJ (neuromuscular junction) formation. We show that the RING domain of rapsyn contains E3 ligase activity. Mutation of the RING domain that abolishes the enzyme activity inhibits rapsyn- as well as agrin-induced AChR clustering in heterologous and muscle cells. Further biological and genetic studies support a working model where rapsyn, a classic scaffold protein, serves as an E3 ligase to induce AChR clustering and NMJ formation, possibly by regulation of AChR neddylation. This study identifies a previously unappreciated enzymatic function of rapsyn and a role of neddylation in synapse formation, and reveals a potential target of therapeutic intervention for relevant neurological disorders.

Keywords

rapsyn
AChR
RING domain
neddylation
E3 ligase

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