Mechanisms of kinetic stabilization by the drugs paclitaxel and vinblastine

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...

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Bibliographic Details
Published in:Molecular biology of the cell 2017-05, Vol.28 (9), p.1238-1257
Main Authors: Castle, Brian T, McCubbin, Seth, Prahl, Louis S, Bernens, Jordan N, Sept, David, Odde, David J
Format: Article
Language:English
Subjects:
Animals
Computer Simulation
Image Processing, Computer-Assisted
Kinetics
Microscopy, Fluorescence - methods
Microtubule-Associated Proteins - metabolism
Microtubules - metabolism
Microtubules - physiology
Paclitaxel - pharmacology
Swine
Thermodynamics
Tubulin - metabolism
Vinblastine - pharmacology
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Summary: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.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.E16-08-0567