Mechanisms of kinetic stabilization by the drugs paclitaxel and vinblastine

Brian T. Castle, Seth McCubbin, Louis S. Prahl, Jordan N. Bernens, David Sept, David J. Odde

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Microtubule-targeting agents (MTAs), widely used as biological probes and chemotherapeutic drugs, bind directly to tubulin subunits and "kinetically stabilize" microtubules, suppressing the characteristic self-assembly process of dynamic instability. However, the molecular-level mechanisms of kinetic stabilization are unclear, and the fundamental thermodynamic and kinetic requirements for dynamic instability and its elimination by MTAs have yet to be defined. Here we integrate a computational model for microtubule assembly with nanometer-scale fluorescence microscopy measurements to identify the kinetic and thermodynamic basis of kinetic stabilization by the MTAs paclitaxel, an assembly promoter, and vinblastine, a disassembly promoter. We identify two distinct modes of kinetic stabilization in live cells, one that truly suppresses on-off kinetics, characteristic of vinblastine, and the other a "pseudo" kinetic stabilization, characteristic of paclitaxel, that nearly eliminates the energy difference between the GTP- and GDP-tubulin thermodynamic states. By either mechanism, the main effect of both MTAs is to effectively stabilize the microtubule against disassembly in the absence of a robust GTP cap.

Original languageEnglish (US)
Pages (from-to)1238-1257
Number of pages20
JournalMolecular biology of the cell
Volume28
Issue number9
DOIs
StatePublished - May 1 2017

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