Insight into Microtubule Catastrophe and Growth




Kim, Tae Hyungmin

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Microtubules are hollow cylindrical polymers of αβ-tubulin that have essential roles segregating chromosomes during cell division, organizing the cytoplasm, establishing cellular polarity, and more. These fundamental activities depend critically on dynamic instability, the stochastic switching of microtubules between phases of growth and rapid shrinking. Dynamic instability is itself a consequence of αβ-tubulin GTPase activity and how it affects interactions between αβ-tubulin in the lattice and at the microtubule end. Although predictive molecular understanding of catastrophe remains elusive, the broad outlines of an understanding have been established. Unpolymerized, GTP-bound αβ-tubulin subunits readily associate at the growing tips of the MTs. Once they are incorporated into the lattice, αβ-tubulin GTPase activity is accelerated. The assembly dependence of GTPase activity results in a "stabilizing cap" of GTP-bound αβ-tubulin near the ends of the growing microtubules. Loss of this stabilizing cap triggers catastrophe, the switch from growth to rapid shrinking, because it exposes the more labile GDP-bound microtubule lattice. And, regaining this GTP cap results in microtubule rescue, the switch from shrinking to growing phase. In Chapter 1, I discuss literature background for microtubule dynamics. In Chapter 2, I present a study in which I explored the molecular mechanism behind microtubule catastrophe using computer simulations. By incorporating various candidates for "missing biochemistry" into the computational models, I discovered that lateral long-range interdimer interactions are crucial in correctly predicting catastrophe frequency as a function of the soluble tubulin concentration. In Chapter 3, I discuss a study that directly measures the αβ-tubulin association and dissociation at the microtubule end. We found that the kinetic on-rate of tubulin dimer to a growing microtubule end may be much smaller than previously thought. Next, in chapter 4, I present studies that explore various factors that affect microtubule shrinking and rescue. Finally, in chapter 5, I will summarize my work on these projects and discuss future directions and preliminary results looking to better understand microtubule dynamics.

General Notes

Pages ii-xi are misnumbered as pages i-x.

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