Autoinhibition of a Neuronal Kinesin UNC-104/KIF1A Regulates the Size and Density of Synapses.
Autoinhibition of a Neuronal Kinesin UNC-104/KIF1A Regulates the Size and Density of Synapses.
复制标题
DOI：
10.1016/j.celrep.2016.07.043
复制
发表时间：
2016-08-23
期刊：
影响因子：
8.8
通讯作者：
Shen K
中科院分区：
文献类型：
--
作者：
Niwa S;Lipton DM;Morikawa M;Zhao C;Hirokawa N;Lu H;Shen K
驱动蛋白马达蛋白通过水解ATP并沿沿着微管轨道移动来将细胞内货物运输到整个细胞。分子内的自抑制相互作用已被证明为几个驱动蛋白在体外，然而，自抑制的生理意义仍然知之甚少。在这里，我们确定了四个突变的柄区和运动域的突触囊泡驱动蛋白，KIF 1A-104，专门破坏自抑制。这些突变增加了微管和货物囊泡在体外的结合。在体内，这些突变导致突触-104的过度激活，导致突触密度降低、突触变小和突触囊泡在树突中的异位定位。我们还表明，突触囊泡结合的小GTADARL-8通过解锁自抑制激活α-104。这些结果表明，自抑制机制是用来调节运输货物的分布，是重要的突触在体内。
Kinesin motor proteins transport intracellular cargos throughout cells by hydrolyzing ATP and moving along microtubule tracks. Intramolecular autoinhibitory interactions have been shown for several kinesins in vitro, however, the physiological significance of autoinhibition remains poorly understood. Here, we identified four mutations in the stalk region and motor domain of synaptic vesicle kinesin, UNC-104/KIF1A, that specifically disrupt autoinhibition. These mutations augment both microtubule and cargo vesicle binding in vitro. In vivo, these mutations cause excessive activation of UNC-104, leading to decreased synaptic density, smaller synapses and ectopic localization of synaptic vesicles in the dendrite. We also show that the synaptic vesicle bound small GTPase ARL-8 activates UNC-104 by unlocking the autoinhibition. These results demonstrate that the autoinhibitory mechanism is utilized to regulate the distribution of transport cargoes and is important for synaptogenesis in vivo.