The mechanism of kinesin inhibition by kinesin-binding protein.
The mechanism of kinesin inhibition by kinesin-binding protein.
复制标题
驱动蛋白结合蛋白抑制运动蛋白的机制。
DOI：
10.7554/elife.61481
复制
发表时间：
2020-11-30
期刊：
影响因子：
7.7
通讯作者：
Moores CA
中科院分区：
文献类型：
--
作者：
Atherton J;Hummel JJ;Olieric N;Locke J;Peña A;Rosenfeld SS;Steinmetz MO;Hoogenraad CC;Moores CA
亚细胞区室化是真核细胞功能所必需的。驱动蛋白活性的时空调节对于通过控制细胞内货物分布来构建这些局部环境是必不可少的。驱动蛋白结合蛋白（KBP）通过其马达结构域与驱动蛋白的一个子集相互作用，抑制其微管（MT）附着，并阻断其细胞功能。然而，其抑制和选择性的机制尚不清楚。在这里，我们使用冷冻电子显微镜揭示KBP和KBP-驱动蛋白运动域复合物的结构。KBP是一个含有三肽重复序列的右旋α-螺线管，其隔离驱动蛋白运动结构域的微管蛋白结合表面，在结构上扭曲运动结构域并在空间上阻断其MT附着。KBP利用其α-螺线管凹面和边缘环结合驱动蛋白运动结构域，并且选择的结构引导突变破坏KBP对细胞中驱动蛋白转运的抑制。KBP相互作用的马达结构域表面包含的图案完全保守的KBP相互作用的驱动蛋白，这表明驱动蛋白的选择性的基础。
Subcellular compartmentalisation is necessary for eukaryotic cell function. Spatial and temporal regulation of kinesin activity is essential for building these local environments via control of intracellular cargo distribution. Kinesin-binding protein (KBP) interacts with a subset of kinesins via their motor domains, inhibits their microtubule (MT) attachment, and blocks their cellular function. However, its mechanisms of inhibition and selectivity have been unclear. Here we use cryo-electron microscopy to reveal the structure of KBP and of a KBP–kinesin motor domain complex. KBP is a tetratricopeptide repeat-containing, right-handed α-solenoid that sequesters the kinesin motor domain’s tubulin-binding surface, structurally distorting the motor domain and sterically blocking its MT attachment. KBP uses its α-solenoid concave face and edge loops to bind the kinesin motor domain, and selected structure-guided mutations disrupt KBP inhibition of kinesin transport in cells. The KBP-interacting motor domain surface contains motifs exclusively conserved in KBP-interacting kinesins, suggesting a basis for kinesin selectivity.