Ultrasensitivity of Microtubule severing rate on the concentration of free Tubulin

Abstract

Cytoskeletal structures aid in cell polarization, motility, and intracellular transport. Their functions are predicated on the rapid turnover of cytoskeleton proteins, which is achieved by the coordinated effort of multiple regulatory proteins whose dynamics is not well understood. Recent in-vitro experiments have investigated mixtures of regulatory proteins and cytoskeletal filaments and have reported novel synergistic effects. For example, free tubulin can repair nanoscale damages of microtubules created by proteins that sever microtubules and, in doing so, affect their disassembly. Based on this observation, we propose a model for microtubule severing as a competition between the processes of damage spreading and tubulin-induced repair. Using theory and simulations, we demonstrate that this model is in quantitative agreement with in vitro experiments. We predict the existence of a critical tubulin concentration above which severing becomes rare but fast. Additionally, we find that microtubule length control via severing with tubulin-induced repair is hypersensitive to changes in the concentration of free tubulin and leads to a dramatically increased dynamic range of filament lengths in steady state. Our work describes how the concerted action of multiple microtubule associated proteins produces novel dynamical properties of these cytoskeletal filaments.Significance StatementHow cytoskeleton-associated proteins coordinate rapid turnover of cytoskeletal structures is not well understood. Recent experiments suggest that microtubule severing is the result of two competing processes of damage spreading and tubulin-induced repair. We find that this process predicts the existence of a critical tubulin concentration above which severing becomes rare but fast, and additionally, a dramatically increased dynamic range of microtubule filament lengths at steady state. This work describes how combining multiple microtubule associated proteins can produce novel dynamical properties which are not seen when these proteins are studied in isolation.

Computer simulation reveals the effect of severing enzymes on dynamic and stabilized microtubules

“…This factor can also be important for tubulin mass and MT number amplification. One of the recent analytical models on severing enzymes considered the severing inhibition due to tubulin concentration [53]. The onset of severing also depends on the temperature, the concentration of ATP, severing enzymes, and free tubulins [27].…”

“…There are a few analytical and computational models for MT amplification and severing [26,[50][51][52][53]. A mathematical model by Kuo et al predicted that the MT amplification after severing happens only if there are stable seeds or MT dynamics shows unbounded growth [26].…”

“…Amplification of longitudinal MTs is observed in plant cells due to controlled plus-end stabilization after severing [51,52]. An analytical model has also been proposed to model the dependence of severing action on free tubulin concentration [53]. However, there is a need for a lattice-based model to understand the amplification and severing of the MTs simultaneously.…”