Taxol acts differently on different tubulin isotypes

Abstract

Taxol is a small molecule effector that allosterically locks tubulin into the microtubule lattice. We report that taxol has different effects on different single isotype microtubule lattices. Using in vitro reconstitution, we show that α1β4 human and zebrafish GDP-tubulin lattices are stabilised and expanded by taxol, whereas α1β3 human GDP-tubulin lattices require tenfold more taxol for stability and are not expanded. In kinesin motility assays, this isotype-specific mechanical action of taxol causes segmented isotype microtubules to deviate into loops, because the expanded β4 and compacted β3 segments try to glide at different rates. To explain, we propose that taxol switches GDP-microtubules into one of two different lattice-mechanical states, a compacted/slow-gliding state or an expanded/fast-gliding state, with switching to the expanded/fast-gliding state dependant on taxol occupancy and available to only some tubulin isotypes. In mixed isotype lattices, we find evidence that this lattice-mechanical switching occurs cooperatively.