Kinesin is an evolutionarily fine-tuned molecular ratchet-and-pawl device of decisively locked direction.
Kinesin is an evolutionarily fine-tuned molecular ratchet-and-pawl device of decisively locked direction.
复制标题
DOI：
10.1529/biophysj.107.108233
复制
发表时间：
2007-11
影响因子：
3.4
通讯作者：
Zhisong Wang;M. Feng;Wenwei Zheng;Dagong Fan
中科院分区：
文献类型：
--
作者：
Zhisong Wang;M. Feng;Wenwei Zheng;Dagong Fan
传统的驱动蛋白是一种二聚体的马达蛋白，其将膜性细胞器运输到微管（MT）的正端。单个驱动蛋白二聚体显示出稳定的方向性和数百个连续的步骤，但详细的物理机制仍不清楚。在这里，我们计算自由能为整个二聚体MT系统的所有可能的相互作用的配置，充分考虑到分子的细节。仅仅采用第一性原理和几个测量的结合能和势垒能，系统级分析揭示了配置之间的不可逾越的能隙，机械解除构型简并引起的不对称基态，和禁止的转换，确保两个电机域之间的协调交替催化。这种丰富的物理效应将驱动蛋白二聚体转化为分子棘轮和棘爪装置，其确定地将二聚体的运动锁定到MT加端，并确保双手交替步态中的连续步骤。然而，在一定范围的极端载荷下，棘轮和棘爪装置变得有缺陷，但并没有完全废除，以允许连续的后退。这项研究得到了定量的证据，驱动蛋白的多种分子特性已经进化适应微调棘轮和棘爪装置，以确保电机的杰出性能。
Conventional kinesin is a dimeric motor protein that transports membranous organelles toward the plus-end of microtubules (MTs). Individual kinesin dimers show steadfast directionality and hundreds of consecutive steps, yet the detailed physical mechanism remains unclear. Here we compute free energies for the entire dimer-MT system for all possible interacting configurations by taking full account of molecular details. Employing merely first principles and several measured binding and barrier energies, the system-level analysis reveals insurmountable energy gaps between configurations, asymmetric ground state caused by mechanically lifted configurational degeneracy, and forbidden transitions ensuring coordination between both motor domains for alternating catalysis. This wealth of physical effects converts a kinesin dimer into a molecular ratchet-and-pawl device, which determinedly locks the dimer's movement into the MT plus-end and ensures consecutive steps in hand-over-hand gait. Under a certain range of extreme loads, however, the ratchet-and-pawl device becomes defective but not entirely abolished to allow consecutive back-steps. This study yielded quantitative evidence that kinesin's multiple molecular properties have been evolutionarily adapted to fine-tune the ratchet-and-pawl device so as to ensure the motor's distinguished performance.