Calcium can mobilize and activate myosin-VI
Calcium can mobilize and activate myosin-VI
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DOI：
10.1073/pnas.1519435113
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发表时间：
2016-03-01
影响因子：
11.1
通讯作者：
Veigel, Claudia
中科院分区：
文献类型：
--
作者：
Batters, Christopher;Brack, Dario;Veigel, Claudia
协调马达蛋白激活的时间的能力位于广泛的细胞运动过程的中心，包括内吞作用、细胞分裂和癌细胞迁移。我们发现，钙显着改变的肌球蛋白-VI电机牵连在这些过程的关键步骤的构象和活动。我们解决了电机构象和结构灵活性的变化，使用单粒子分析的电子显微镜数据，并确定相互作用的领域，使用荧光光谱。我们发现，钙结合钙调蛋白的结合亲和力增加了2,500倍的一个双向结合位点的肌球蛋白VI。钙-钙调蛋白在结合位点组分之间寻找和桥接的能力指导马达从紧凑的休眠状态到非运动的货物结合启动状态的主要重排。在高钙时缺乏运动性是由于钙调素转换到更高亲和力的结合位点，这使得原始的IQ基序暴露，从而使杠杆臂不稳定。回到低钙可以重新稳定杠杆臂，这是将货物结合的马达转移到细胞中心所需的，或者将无货物马达重新折叠成非活性状态，为下一次细胞钙流量做好准备。
The ability to coordinate the timing of motor protein activation lies at the center of a wide range of cellular motile processes including endocytosis, cell division, and cancer cell migration. We show that calcium dramatically alters the conformation and activity of the myosin-VI motor implicated in pivotal steps of these processes. We resolved the change in motor conformation and in structural flexibility using single particle analysis of electron microscopic data and identified interacting domains using fluorescence spectroscopy. We discovered that calcium binding to calmodulin increases the binding affinity by a factor of 2,500 for a bipartite binding site on myosin-VI. The ability of calcium-calmodulin to seek out and bridge between binding site components directs a major rearrangement of the motor from a compact dormant state into a cargo binding primed state that is nonmotile. The lack of motility at high calcium is due to calmodulin switching to a higher affinity binding site, which leaves the original IQ-motif exposed, thereby destabilizing the lever arm. The return to low calcium can either restabilize the lever arm, required for translocating the cargo-bound motors toward the center of the cell, or refold the cargo-free motors into an inactive state ready for the next cellular calcium flux.