Molecular and Mechanical Causes of Microtubule Catastrophe and Aging

Abstract

Tubulin polymers, microtubules, can switch abruptly from the assembly to shortening. These infrequent transitions, termed "catastrophes", affect numerous cellular processes but the underlying mechanisms are elusive. We approached this complex stochastic system using advanced coarse-grained molecular dynamics modeling of tubulin-tubulin interactions. Unlike in previous simplified models of dynamic microtubules, the catastrophes in this model arise owing to fluctuations in the composition and conformation of a growing microtubule tip, most notably in the number of protofilament curls. In our model, dynamic evolution of the stochastic microtubule tip configurations over a long timescale, known as the system's "aging", gives rise to the nonexponential distribution of microtubule lifetimes, consistent with experiment. We show that aging takes place in the absence of visible changes in the microtubule wall or tip, as this complex molecular-mechanical system evolves slowly and asymptotically toward the steady-state level of the catastrophe-promoting configurations. This new, to our knowledge, theoretical basis will assist detailed mechanistic investigations of the mechanisms of action of different microtubule-binding proteins and drugs, thereby enabling accurate control over the microtubule dynamics to treat various pathologies.

Termination of Protofilament Elongation by Eribulin Induces Lattice Defects that Promote Microtubule Catastrophes

“…Interestingly, we also occasionally observed indications of protofilament blocking in control microtubules in the absence of any drugs, an effect that could contribute to naturally occurring catastrophes. Previous work has shown that the catastrophe frequency might reflect the accumulation of structural defects, such as plus-end tapering due to asynchronously growing protofilaments [1][2][3][4]. Strikingly, we found that the behavior of a pre-catastrophe microtubule tip in control microtubules is similar to the ones that are expected to lack protofilaments after Eribulin binding: in both cases the growth rate, the EB3 comet intensity and the straightness index were reduced.…”

“…Asynchronous elongation of individual protofilaments can potentially lead to an altered microtubule-end structure that promotes sudden depolymerization, termed catastrophe [1][2][3][4]. However, how the dynamics of individual protofilaments relates to overall growth persistence has remained unclear.…”

GDP-to-GTP exchange on the microtubule end can contribute to the frequency of catastrophe

“…, 2002, 2005; Coombes et al. , 2013), and others (Zakharov et al. , 2015) all share some version of a cis -acting nucleotide.…”

Microtubule: a dynamically unstable stochastic phase switching polymer

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