MPI Campus Seminar: Subnanometer Mechanics of Microtubule Dynamic Instability

Microtubules (MTs) are one of the major components of the eukaryotic cytoskeleton and essential for intracellular transport, cell motility, and chromosome segregation during mitosis. These are filamentous assemblies of tubulin dimers stacked head-to tail in polar protofilaments and folded into hollow tubes via lateral interactions. The metastable nature of MTs has been a long-standing problem for cell scientists. Both MT assembly and disassembly operate via subtle changes in the shape of tubulins and accumulation of mechanical tension, either allosterically or fueled by GTP hydrolysis. However, it is still elusive how and where these shape changes contribute to the life cycle of a MT. In our work, we study the conformational dynamics of tubulin both in unassembled and polymerized states, using a combination of cryo-EM and intensive atomistic simulations. It is first demonstrated how the nucleotide state of tubulin is linked to its dynamics and energetics in solution and why GTP-induced flexibility is crucial to MT assembly. Using accurate atomistic MT models refined against near-atomic cryo-EM data, we then interrogate the destabilizing impacts of GTP hydrolysis on the MT lattice. We show that a large portion of hydrolysis energy is stored in the lattice in the form of intrinsic mechanical strain, which is released upon MT disassembly. Taken together, a model of MT instability emerges in which MT (dis)assembly is not exclusively driven by the nucleotidedependent dynamics of individual tubulins, but more generally, by their concerted collective behavior.