Molecular basis for specific regulation of neuronal kinesin-3 motors by doublecortin family proteins.
Molecular basis for specific regulation of neuronal kinesin-3 motors by doublecortin family proteins.
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DOI：
10.1016/j.molcel.2012.06.025
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发表时间：
2012-09-14
期刊：
影响因子：
16
通讯作者：
Walsh, Christopher A.
中科院分区：
文献类型：
--
作者：
Liu, Judy S.;Schubert, Christian R.;Fu, Xiaoqin;Fourniol, Franck J.;Jaiswal, Jyoti K.;Houdusse, Anne;Stultz, Collin M.;Moores, Carolyn A.;Walsh, Christopher A.
双皮质素（Dcx）定义了一个正在增长的微管（MT）相关蛋白（MAPs）家族，参与神经元迁移和过程生长。我们发现Dcx对于Kif1a的功能至关重要，Kif1a是一种运输突触囊泡的运动蛋白。缺乏Dcx和/或其结构保守的旁联物双皮质素样激酶1 （Dclk1）的神经元显示Kif1a介导的Vamp2运输受损，Kif1a的货物，运行长度减少。Dcx连接子序列中的人类疾病相关突变（如W146C、K174E）通过破坏Dcx/Kif1a相互作用而不影响Dcx MT结合来改变Kif1a/Vamp2转运。低温电子显微镜和亚纳米分辨率图像重建揭示了mt结合Dcx依赖于激酶的构象变变性，并提出了MTs上MAP-motor串串的模型。map改变激酶运行长度代表了一种以前未被发现的控制激酶转运的模式，并提供了一种通过局部信号调节基于mt的转运的机制。►Dcx增加了Kif1a/Vamp2的运行长度而不影响传统的kinesin►Dcx增强了adp结合的Kif1a马达结构域对微管的亲和力►Kif1a微管结合需要位移柔性Dcx结构域连接体
Doublecortin (Dcx) defines a growing family of microtubule (MT)-associated proteins (MAPs) involved in neuronal migration and process outgrowth. We show that Dcx is essential for the function of Kif1a, a kinesin-3 motor protein that traffics synaptic vesicles. Neurons lacking Dcx and/or its structurally conserved paralogue, doublecortin-like kinase 1 (Dclk1), show impaired Kif1a-mediated transport of Vamp2, a cargo of Kif1a, with decreased run length. Human disease-associated mutations in Dcx's linker sequence (e.g., W146C, K174E) alter Kif1a/Vamp2 transport by disrupting Dcx/Kif1a interactions without affecting Dcx MT binding. Dcx specifically enhances binding of the ADP-bound Kif1a motor domain to MTs. Cryo-electron microscopy and subnanometer-resolution image reconstruction reveal the kinesin-dependent conformational variability of MT-bound Dcx and suggest a model for MAP-motor crosstalk on MTs. Alteration of kinesin run length by MAPs represents a previously undiscovered mode of control of kinesin transport and provides a mechanism for regulation of MT-based transport by local signals. ► Dcx is required for neuronal transport mediated by the kinesin-3 motor Kif1a ► Dcx increases Kif1a/Vamp2 run length without affecting conventional kinesin ► Dcx enhances the affinity of the ADP-bound Kif1a motor domain for microtubules ► Kif1a microtubule binding requires displacement of the flexible Dcx domain linker
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DOI：
10.1083/jcb.200601067
发表时间：
2006-05-22
期刊：
The Journal of cell biology
影响因子：
--
作者：
Glater EE;Megeath LJ;Stowers RS;Schwarz TL
通讯作者：
Schwarz TL
影响因子：
16.2
作者：
Jacobson, C;Schnapp, B;Banker, GA
通讯作者：
Banker, GA
DOI：
10.1073/pnas.97.16.9287
发表时间：
2000-08-01
影响因子：
11.1
作者：
Feng, J;Yan, Z;Greengard, P
通讯作者：
Greengard, P
影响因子：
16.2
作者：
Koizumi, H;Tanaka, T;Gleeson, JG
通讯作者：
Gleeson, JG
影响因子：
25
作者：
Bai, JL;Ramos, RL;LoTurco, JJ
通讯作者：
LoTurco, JJ