A physical model describing the transport mechanisms of cytoplasmic dynein

Trott, Laurie Elizabeth (2017) A physical model describing the transport mechanisms of cytoplasmic dynein. Doctoral thesis (PhD), University of Sussex.

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Cytoplasmic dynein 1 is crucial for many cellular processes including endocytosis and cell division.
Dynein malfunction can lead to neurodevelopmental and neurodegenerative disease, such
as intellectual disability, Charcot-Marie-Tooth disease and spinal muscular atrophy with lower extremity
predominance. We formulate, based on physical principles, a mechanical model to describe
the stepping behaviour of cytoplasmic dynein walking on microtubules. 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 components such as the cargo (for example an
endosome or bead), two rings of six ATPase domains associated with diverse cellular activities and
the microtubule binding domains. This mathematical framework allows us to examine experimental
observations across different species of dynein as well as being able to make predictions (not
currently experimentally measured) on the temporal behaviour of the individual components of

Initially, we examine a continuous model using plausible force functions to model the ATP force
and binding affinity to the microtubule. Our results show hand-over-hand and shuffling stepping
patterns in agreement with experimental observations. We are able to move from a hand-overhand
to a shuffling stepping pattern by changing a single parameter. We also explore the effects
of multiple motors.

Next, we explore stochasticity within the model, modelling the binding of ATP as a random
event. Our results reflect experimental observations that dynein walks using a predominantly
shuffling stepping pattern. Furthermore, we study the effects of mutated dynein and extend the
model to include variable step sizes, backward stepping and dwelling. Independent stepping is
studied and the results show that coordinated stepping is needed in order to obtain experimental
run lengths.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Mathematical and Physical Sciences > Mathematics
Subjects: Q Science > QH Natural history > QH0301 Biology > QH0573 Cytology
Depositing User: Library Cataloguing
Date Deposited: 30 Jan 2017 09:27
Last Modified: 30 Jan 2017 09:27
URI: http://sro.sussex.ac.uk/id/eprint/66461

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