Trott L, Hafezparast M, Madzvamuse A
Department of Mathematics, School of Mathematical and Physical Sciences, University of Sussex, Brighton BN1 9QH, UK.
School of Life Sciences, University of Sussex, Brighton BN1 9QH, UK.
R Soc Open Sci. 2018 Aug 8;5(8):171568. doi: 10.1098/rsos.171568. eCollection 2018 Aug.
Cytoplasmic dynein 1 (hereafter referred to simply as dynein) is a dimeric motor protein that walks and transports intracellular cargos towards the minus end of microtubules. In this article, we formulate, based on physical principles, a mechanical model to describe the stepping behaviour of cytoplasmic dynein walking on microtubules from the cell membrane towards the nucleus. Unlike previous studies on physical models of this nature, we base our formulation on the whole structure of dynein to include the temporal dynamics of the individual subunits such as the cargo (for example, an endosome, vesicle or bead), two rings of six ATPase domains associated with diverse cellular activities (AAA+ rings) and the microtubule-binding domains which allow dynein to bind to microtubules. This mathematical framework allows us to examine experimental observations on dynein across a wide range of different species, as well as being able to make predictions on the temporal behaviour of the individual components of dynein not currently experimentally measured. Furthermore, we extend the model framework to include backward stepping, variable step size and dwelling. The power of our model is in its predictive nature; first it reflects recent experimental observations that dynein walks on microtubules using a weakly coordinated stepping pattern with predominantly not passing steps. Second, the model predicts that interhead coordination in the ATP cycle of cytoplasmic dynein is important in order to obtain the alternating stepping patterns and long run lengths seen in experiments.
细胞质动力蛋白1（以下简称为动力蛋白）是一种二聚体马达蛋白，它沿着微管向负极行走并运输细胞内货物。在本文中，我们基于物理原理构建了一个力学模型，以描述细胞质动力蛋白从细胞膜向细胞核在微管上行走的步进行为。与以往关于此类物理模型的研究不同，我们的模型构建基于动力蛋白的整体结构，包括各个亚基的时间动态，如货物（例如，内体、囊泡或珠子）、与多种细胞活动相关的两个由六个ATP酶结构域组成的环（AAA+环）以及使动力蛋白能够结合微管的微管结合结构域。这个数学框架使我们能够研究不同物种中关于动力蛋白的实验观察结果，并且能够对目前尚未通过实验测量的动力蛋白各个组分的时间行为进行预测。此外，我们扩展了模型框架，以纳入向后步进、可变步长和停留。我们模型的强大之处在于其预测性质；首先，它反映了最近的实验观察结果，即动力蛋白在微管上行走时采用弱协调的步进模式，主要是不通过步。其次，该模型预测，细胞质动力蛋白ATP循环中的头部间协调对于获得实验中观察到的交替步进模式和长行程长度很重要。
