Center for Theoretical Biological Physics, Rice University, Houston, TX 77005.
Department of Physical Chemistry, Indian Association for the Cultivation of Science, Jadavpur, 700032 Kolkata, India.
Proc Natl Acad Sci U S A. 2018 Oct 2;115(40):10052-10057. doi: 10.1073/pnas.1806688115. Epub 2018 Sep 17.
Cytoplasmic dyneins play a major role in retrograde cellular transport by moving vesicles and organelles along microtubule filaments. Dyneins are multidomain motor proteins with two heads that coordinate their motion via their interhead tension. Compared with the leading head, the trailing head has a higher detachment rate from microtubules, facilitating the movement. However, the molecular mechanism of such coordination is unknown. To elucidate this mechanism, we performed molecular dynamics simulations on a cytoplasmic dynein with a structure-based coarse-grained model that probes the effect of the interhead tension on the structure. The tension creates a torque that influences the head rotating about its stalk. The conformation of the stalk switches from the α registry to the β registry during the rotation, weakening the binding affinity to microtubules. The directions of the tension and the torque of the leading head are opposite to those of the trailing head, breaking the structural symmetry between the heads. The leading head transitions less often to the β registry than the trailing head. The former thus has a greater binding affinity to the microtubule than the latter. We measured the moment arm of the torque from a dynein structure in the simulations to develop a phenomenological model that captures the influence of the head rotating about its stalk on the differential detachment rates of the two heads. Our study provides a consistent molecular picture for interhead coordination via interhead tension.
细胞质动力蛋白在逆行细胞运输中起着重要作用，通过沿微管丝移动囊泡和细胞器。动力蛋白是具有两个头部的多结构域运动蛋白，通过它们的头部间张力协调它们的运动。与前导头部相比，尾随头部从微管上的脱离率更高，从而促进了运动。然而，这种协调的分子机制尚不清楚。为了阐明这种机制，我们使用基于结构的粗粒化模型对细胞质动力蛋白进行了分子动力学模拟，该模型探测了头部间张力对结构的影响。张力产生的扭矩会影响头部围绕其茎的旋转。在旋转过程中，茎的构象从α构象转变为β构象，从而削弱与微管的结合亲和力。前导头部的张力和扭矩方向与尾随头部相反，打破了头部之间的结构对称性。前导头部比尾随头部更不容易转换为β构象。因此，前导头部与微管的结合亲和力大于尾随头部。我们从模拟中的动力蛋白结构测量了扭矩的力臂，以开发一个唯象模型，该模型捕获了头部围绕其茎旋转对两个头部的差异脱离率的影响。我们的研究通过头部间张力提供了一个一致的分子图景，用于头部间的协调。
