How Cytoplasmic Dynein Couples ATP Hydrolysis Cycle to Diverse Stepping Motions: Kinetic Modeling
How Cytoplasmic Dynein Couples ATP Hydrolysis Cycle to Diverse Stepping Motions: Kinetic Modeling
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细胞质动力蛋白如何将 ATP 水解循环与多种步进运动耦合：动力学模型
DOI：
10.1016/j.bpj.2020.03.012
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发表时间：
2020
影响因子：
3.4
通讯作者：
Takada Shoji
中科院分区：
文献类型：
--
作者：
Kubo Shintaroh;Shima Tomohiro;Takada Shoji
细胞质动力蛋白是一种双头分子马达，通过ATP水解自由能运动到微管的负端。通过使用它的两个头（电机域），细胞质动力蛋白表现出各种双足步进运动：尺蠖和手在手上的运动，以及一个头的非交替步骤。然而，由于缺乏同时观察动力蛋白的步进和ATP酶反应的实验方法，实现这种不同步进方式的分子基础仍然不清楚。在这里，我们提出了一个动力学模型的细胞质动力蛋白的双足运动，并进行吉莱斯皮蒙特卡罗模拟，定性再现迄今为止获得的大多数实验数据。该模型表示的每个电机域的状态为五个状态，根据构象和核苷酸和微管结合条件的域。此外，两个区域的相对位置被近似为三个离散状态。伴随着ATP水解循环，动力蛋白stochemical和proctomic模型向前移动，通过不同的途径，包括尺蠖和手在手的运动，类似于实验数据的多个步骤。该模型再现了与运动性相关的关键实验性质，包括速度和运行长度，作为ATP浓度和外力的函数，因此为动力蛋白如何实现各种步进方式以及核苷酸状态的明确表征提供了合理的解释。我们的模型突出了独特的动力蛋白在耦合的ATP酶与它的运动在尺蠖和手在手步进。
Cytoplasmic dynein is a two-headed molecular motor that moves to the minus end of a microtubule by ATP hydrolysis free energy. By employing its two heads (motor domains), cytoplasmic dynein exhibits various bipedal stepping motions: inchworm and hand-over-hand motions, as well as nonalternating steps of one head. However, the molecular basis to achieve such diverse stepping manners remains unclear because of the lack of an experimental method to observe stepping and the ATPase reaction of dynein simultaneously. Here, we propose a kinetic model for bipedal motions of cytoplasmic dynein and perform Gillespie Monte Carlo simulations that qualitatively reproduce most experimental data obtained to date. The model represents the status of each motor domain as five states according to conformation and nucleotide- and microtubule-binding conditions of the domain. In addition, the relative positions of the two domains were approximated by three discrete states. Accompanied by ATP hydrolysis cycles, the model dynein stochastically and processively moved forward in multiple steps via diverse pathways, including inchworm and hand-over-hand motions, similarly to experimental data. The model reproduced key experimental motility-related properties, including velocity and run length, as functions of the ATP concentration and external force, therefore providing a plausible explanation of how dynein achieves various stepping manners with explicit characterization of nucleotide states. Our model highlights the uniqueness of dynein in the coupling of ATPase with its movement during both inchworm and hand-over-hand stepping.