Long-range, Through-Lattice Coupling Improves Predictions of Microtubule Catastrophe

Mol Biol Cell. 2019 Jun 1;30(12):1451-1462. doi: 10.1091/mbc.E18-10-0641. Epub 2019 Apr 3.

Abstract

Microtubules are cylindrical polymers of αβ-tubulin that play critical roles in fundamental processes such as chromosome segregation and vesicular transport. Microtubules display dynamic instability, switching stochastically between growth and rapid shrinking as a consequence of GTPase activity in the lattice. The molecular mechanisms behind microtubule catastrophe, the switch from growth to rapid shrinking, remain poorly defined. Indeed, two-state stochastic models that seek to describe microtubule dynamics purely in terms of the biochemical properties of GTP- and GDP-bound αβ-tubulin predict the concentration dependence of microtubule catastrophe incorrectly. Recent studies provide evidence for three distinct conformations of αβ-tubulin in the lattice that likely correspond to GTP, GDP.Pi, and GDP. The incommensurate lattices observed for these different conformations raise the possibility that in a mixed nucleotide state lattice, neighboring tubulin dimers might modulate each other's conformations and hence each other's biochemistry. We explored whether incorporating a GDP.Pi state or the likely effects of conformational accommodation can improve predictions of catastrophe. Adding a GDP.Pi intermediate did not improve the model. In contrast, adding neighbor-dependent modulation of tubulin biochemistry improved predictions of catastrophe. Because this conformational accommodation should propagate beyond nearest-neighbor contacts, our modeling suggests that long-range, through-lattice effects are important determinants of microtubule catastrophe.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Computer Simulation
  • GTP Phosphohydrolases / metabolism
  • Guanosine Diphosphate / metabolism
  • Microtubules / metabolism*
  • Models, Biological
  • Tubulin / metabolism

Substances

  • Tubulin
  • Guanosine Diphosphate
  • GTP Phosphohydrolases