Abstract
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.
Highlights
Cytoplasmic dynein 1 is a protein complex which moves in the centripetal direction along& 2018 The Authors
The devastating effect of dynein malfunction presented in mutation studies on mouse models as well as in humans shows the need for greater understanding of the mechanics and processes used by dynein [8,9,10,13]
Variable step sizes are explored in §5.4; they are restricted to multiples of 8 nm to ensure that they can only bind at a specified binding site on the microtubule
Summary
Cytoplasmic dynein 1 (hereafter referred to as dynein) is a protein complex which moves in the centripetal direction along. The stalk-coiled coil acts as a communication pathway between the AAA rings and the MTBDs. It must be noted that dynein-driven transport of cargos along microtubules requires other components such as the cofactor dynactin and other regulatory proteins [1,2,28]. We will not take into account other complex processes associated with dynein structure and function and these include the role of cofactors in the dynein transport mechanism, dynein auto-inhibition and activation (by phi-particle, for example), etc. Integrating the temporal dynamics of the individual components that include the cargo, tail domain, AAAþ rings and MTBDs. For simplicity, we formulate our modelling on a one-dimensional microtubule, leaving extensions to multi-dimensions for future studies.
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