Department of Cellular Biochemistry, University Medical Center Goettingen, Georg-August-University Göttingen, Humboldtallee 23, 37073, Göttingen, Germany.
The Max-Planck-Institute for Experimental Medicine, Proteomics, Hermann-Rein-Str. 3, 37073, Göttingen, Germany.
Sci Rep. 2017 Nov 17;7(1):15781. doi: 10.1038/s41598-017-16055-4.
AP-1/σ1B-deficiency causes X-linked intellectual disability. AP-1/σ1B -/- mice have impaired synaptic vesicle recycling, fewer synaptic vesicles and enhanced endosome maturation mediated by AP-1/σ1A. Despite defects in synaptic vesicle recycling synapses contain two times more endocytic AP-2 clathrin-coated vesicles. We demonstrate increased formation of two classes of AP-2/clathrin coated vesicles. One which uncoats readily and a second with a stabilised clathrin coat. Coat stabilisation is mediated by three molecular mechanisms: reduced recruitment of Hsc70 and synaptojanin1 and enhanced μ2/AP-2 phosphorylation and activation. Stabilised AP-2 vesicles are enriched in the structural active zone proteins Git1 and stonin2 and synapses contain more Git1. Endocytosis of the synaptic vesicle exocytosis regulating Munc13 isoforms are differentially effected. Regulation of synaptic protein endocytosis by the differential stability of AP-2/clathrin coats is a novel molecular mechanism of synaptic plasticity.
AP-1/σ1B 缺陷导致 X 连锁智力障碍。AP-1/σ1B -/- 小鼠的突触囊泡再循环受损，突触囊泡较少，AP-1/σ1A 介导的内体成熟增强。尽管突触囊泡再循环存在缺陷，但突触中含有两倍以上的内吞作用的 AP-2 网格蛋白包被小泡。我们证明了两种 AP-2/网格蛋白包被小泡的形成增加。一种很容易解聚，另一种则具有稳定的网格蛋白涂层。涂层稳定是通过三种分子机制介导的：Hsc70 和 synaptojanin1 的募集减少，以及 μ2/AP-2 的磷酸化和激活增强。稳定的 AP-2 小泡富含结构活性区蛋白 Git1 和 stonin2，并且突触中含有更多的 Git1。调节突触囊泡胞吐作用的突触蛋白内吞作用的 Munc13 异构体受到不同的影响。AP-2/网格蛋白涂层的稳定性差异调节突触蛋白内吞作用是突触可塑性的一种新的分子机制。
