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 journalArticlepeer-review

28 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

Bibliographical note

Funding Information:
B.T.C. was supported by National Institutes of Health Fellowship T32 EB008389. S.M. was supported by National Institutes of Health Fellowship T32 GM008270. L.S.P. was supported by a 3M Science & Technology Doctoral Fellowship through the University of Minnesota and National Science Foundation Graduate Research Fellowship 00039202. The research was supported by National Institutes of Health grants R01 GM071522 to D.J.O. and R01 GM076177 to D.S. and D.J.O.

Publisher Copyright:
© 2017 Castle et al.

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