The crystal structure and biochemical characterization of Kif15: a bifunctional molecular motor involved in bipolar spindle formation and neuronal development.
The crystal structure and biochemical characterization of Kif15: a bifunctional molecular motor involved in bipolar spindle formation and neuronal development.
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DOI：
10.1107/s1399004713028721
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发表时间：
2014-01
期刊：
影响因子：
--
通讯作者：
Kozielski F
中科院分区：
文献类型：
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作者：
Klejnot M;Falnikar A;Ulaganathan V;Cross RA;Baas PW;Kozielski F
Kif15的结构和生物化学研究提供了对这种潜在药物靶点的深入了解，并允许与Eg5进行比较，Eg5是一种部分共享Kif15功能的驱动蛋白。驱动蛋白是一个以微管为基础的马达蛋白超家族，具有从细胞内运输到细胞分裂的重要细胞功能。一些驱动蛋白家族成员在真核细胞周期的有丝分裂期发挥作用，并且对于细胞分裂的成功进行至关重要。在有丝分裂的早期，在前中期，某些驱动蛋白是形成双极纺锤体所必需的，如Eg5和Kif15，它们似乎具有部分重叠的功能。由于驱动蛋白将ATP水解产生的化学能转化为机械功，因此抑制其功能是药物开发的一种易于处理的方法。靶向Eg5的药物已显示出作为抗癌剂的前景。Kif15最近脱颖而出，因为它可以取代Eg5的功能，并且本身可能具有作为潜在药物靶点的潜力。在这里，Kif15的初始生化，动力学和结构表征的报告，并与功能相关的电机Eg5进行比较。虽然Kif15在催化位点含有ADP，但其马达结构域结构被捕获为“ATP样”构型，颈连接体停靠在催化核心上。还研究了Kif15与微管的相互作用，阐明了这两种马达之间的结构差异，这表明它们的作用模式存在深刻的差异，与目前的微管交联和滑动模型一致。
The structural and biochemical study of Kif15 provides insight into this potential drug target and allows comparison with Eg5, a kinesin that partially shares the functions of Kif15. Kinesins constitute a superfamily of microtubule-based motor proteins with important cellular functions ranging from intracellular transport to cell division. Some kinesin family members function during the mitotic phase of the eukaryotic cell cycle and are crucial for the successful progression of cell division. In the early stages of mitosis, during prometaphase, certain kinesins are required for the formation of the bipolar spindle, such as Eg5 and Kif15, which seem to possess partially overlapping functions. Because kinesins transform the chemical energy from ATP hydrolysis into mechanical work, inhibition of their function is a tractable approach for drug development. Drugs targeting Eg5 have shown promise as anticancer agents. Kif15 has recently come to the fore because it can substitute the functions of Eg5, and may itself have potential as a prospective drug target. Here, the initial biochemical, kinetic and structural characterization of Kif15 is reported and it is compared with the functionally related motor Eg5. Although Kif15 contains ADP in the catalytic site, its motor-domain structure was captured in the ‘ATP-like’ configuration, with the neck linker docked to the catalytic core. The interaction of Kif15 with microtubules was also investigated and structural differences between these two motors were elucidated which indicate profound differences in their mode of action, in agreement with current models of microtubule cross-linking and sliding.