Taxol acts differently on different tubulin isotypes

Abstract

AbstractTaxol is a critically important cancer drug that stabilises microtubules. We report that taxol acts differently on different metazoan tubulin isotypes. 50 nM taxol blocks catastrophe of human or zebrafish α1β4 but has no effect on human α1β3 microtubules. 500 nM taxol blocks catastrophe in both α1β3 and α1β4 microtubules but introduces kinks only into α1β4 microtubules. Taxol washout relaxes the kinks, suggesting taxol expands α1β4 but not α1β3 lattices. Kinesin-driven microtubule gliding detects this conformational shift - α1β4 microtubules glide at ~450 nm/sec in 400 nM taxol, but at ~750 nm/sec in 10 μM taxol, whereas α1β3 microtubules glide at ~450 nm/sec, even in 10 μM taxol. Thus, taxol readily stabilises α1β4 GDP-tubulin lattices and shifts them to a fastgliding conformation, but stabilises α1β3 lattices much less readily and without shifting their conformation. These isotype-specific actions of taxol may drive the switch to β3 tubulin commonly seen in taxol-resistant tumours.