The role of tubulin-tubulin lattice contacts in the mechanism of microtubule dynamic instability

Microtubules form from longitudinally and laterally assembling tubulin α/β-dimers. The assembly induces strain in tubulin, resulting in cycles of microtubule catastrophe and regrowth. This so-called dynamic instability is governed by GTP hydrolysis that renders the microtubule lattice unstable, but it is unclear how. We used the human microtubule nucleating and stabilising neuronal protein doublecortin and high-resolution cryo-EM to capture tubulin’s elusive hydrolysis intermediate GDP.Pi state, alongside the pre-hydrolysis analogue GMPCPP state, and the post-hydrolysis GDP state with and without an anti-cancer drug Taxol®. GTP hydrolysis to GDP.Pi, followed by Pi release, constitute distinct structural transitions, causing unevenly distributed compressions of tubulin dimers, thereby tightening longitudinal and loosening lateral inter-dimer contacts. We conclude that microtubule catastrophe is triggered because the lateral contacts can no longer counteract the strain energy stored in the lattice, while reinforcement of the longitudinal contacts may support generation of force