Enzymatic Activity of the Scaffold Protein Rapsyn for Synapse Formation.
Enzymatic Activity of the Scaffold Protein Rapsyn for Synapse Formation.
复制标题
支架蛋白 Rapsyn 对突触形成的酶活性。
DOI：
10.1016/j.neuron.2016.10.023
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发表时间：
2016-12-07
期刊：
影响因子：
16.2
通讯作者：
Mei L
中科院分区：
文献类型：
--
作者：
Li L;Cao Y;Wu H;Ye X;Zhu Z;Xing G;Shen C;Barik A;Zhang B;Xie X;Zhi W;Gan L;Su H;Xiong WC;Mei L
神经传递是由突触后膜上高浓度的神经递质受体保证的。这是由连接受体和细胞骨架的支架蛋白介导的。其中一种蛋白质是Rapsyn(突触上的受体相关蛋白)，它是乙酰胆碱受体(AChR)聚集和神经肌肉连接(NMJ)形成所必需的。我们发现Rapsyn的环状结构域含有E3连接酶活性。取消酶活性的环域的突变抑制了Rapsyn和agrin诱导的异源细胞和肌肉细胞中的AChR聚集。进一步的生物学和遗传学研究支持一种工作模型，在该模型中，经典的支架蛋白Rapsyn作为E3连接酶，可能通过调节AChR的连接来诱导AChR聚集和NMJ的形成。这项研究确定了以前未被认识的Rapsyn的酶功能以及neddyling在突触形成中的作用，并揭示了相关神经疾病的治疗干预的潜在靶点。
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.