Regulation of synaptic vesicle recycling by complex formation between intersectin 1 and the clathrin adaptor complex AP2
Regulation of synaptic vesicle recycling by complex formation between intersectin 1 and the clathrin adaptor complex AP2
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DOI：
10.1073/pnas.0911073107
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发表时间：
2010-03-02
影响因子：
11.1
通讯作者：
Haucke, Volker
中科院分区：
文献类型：
--
作者：
Pechstein, Arndt;Bacetic, Jelena;Haucke, Volker
网格蛋白介导的突触囊泡（SV）的再循环涉及时空控制组装网格蛋白外壳组件在磷脂酰肌醇（4，5）-二磷酸[ PI（4，5）P-2]-丰富的膜网站内的活动区。需要这种时空控制来协调SV货物分选与网格蛋白/AP 2募集，并抑制膜分裂和突触Janin介导的脱膜，直到膜变形和网格蛋白涂层组装完成。这些控制机制背后的分子事件是未知的。在这里，我们表明，内吞SH 3域含有辅助蛋白intersectin 1支架的内吞过程中直接关联的网格蛋白适配器AP 2。急性扰动的interstin 1-AP 2相互作用在七鳃鳗突触原位抑制SV循环的开始。在结构上，复合物的形成可以归因于在相交蛋白1 SH 3A-B接头区域内的疏水肽与AP 2 α-和β-附属结构域的“侧位点”的直接缔合。SH 3A-B接头区的AP 2附属物结合抑制肌醇磷酸酶synaptojanin 1与intersectin 1的结合。这些数据确定的intersectin-AP 2复合物作为一个重要的调节网格蛋白介导的SV回收突触。
Clathrin-mediated synaptic vesicle (SV) recycling involves the spatiotemporally controlled assembly of clathrin coat components at phosphatidylinositiol (4, 5)-bisphosphate [ PI(4,5)P-2]-enriched membrane sites within the periactive zone. Such spatiotemporal control is needed to coordinate SV cargo sorting with clathrin/AP2 recruitment and to restrain membrane fission and synaptojanin-mediated uncoating until membrane deformation and clathrin coat assembly are completed. The molecular events underlying these control mechanisms are unknown. Here we show that the endocytic SH3 domain-containing accessory protein intersectin 1 scaffolds the endocytic process by directly associating with the clathrin adaptor AP2. Acute perturbation of the intersectin 1-AP2 interaction in lamprey synapses in situ inhibits the onset of SV recycling. Structurally, complex formation can be attributed to the direct association of hydrophobic peptides within the intersectin 1 SH3A-B linker region with the "side sites" of the AP2 alpha- and beta-appendage domains. AP2 appendage association of the SH3A-B linker region inhibits binding of the inositol phosphatase synaptojanin 1 to intersectin 1. These data identify the intersectin-AP2 complex as an important regulator of clathrin-mediated SV recycling in synapses.