Taxanes convert regions of perturbed microtubule growth into rescue sites

Rai, A. and Liu, T. and Glauser, S. and Katrukha, E.A. and Estévez-Gallego, J. and Rodríguez-García, R. and Fang, W.-S. and Díaz, J.F. and Steinmetz, M.O. and Altman, K.-H. and Kapitein, L.C. and Moores, Carolyn A. and Akhmanova, A. (2020) Taxanes convert regions of perturbed microtubule growth into rescue sites. Nature Materials 19 , pp. 355-365. ISSN 1476-1122.

Abstract

Microtubules are polymers of tubulin dimers, and conformational transitions in the microtubule lattice drive microtubule dynamic instability and affect various aspects of microtubule function. The exact nature of these transitions and their modulation by anti -cancer drugs such as Taxol and epothilone, which can stabilize microtubules but also perturb their growth, are poorly understood. Here, we directly visualize the action of fluorescent Taxol and epothilone derivatives and show that microtubules can transition to a state that triggers cooperative drug binding to form regions with altered lattice conformation. Such regions emerge at growing microtubule ends that are in a pre-catastrophe state and inhibit microtubule growth and shortening. Electron microscopy and in vitro dynamics data indicate that taxane accumulation zones represent incomplete tubes that can persist, incorporate tubulin dimers and repeatedly induce microtubule rescues. Thus, taxanes modulate the material properties of microtubules by converting destabilized growing microtubule ends into regions resistant to depolymerization.

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