Taxol acts differently on different tubulin isotypes

Abstract

Taxol 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 1{beta}4 but has no effect on human 1{beta}3 microtubules. 500 nM taxol blocks catastrophe in both 1{beta}3 and 1{beta}4 microtubules but introduces kinks only into 1{beta}4 microtubules. Taxol washout relaxes the kinks, suggesting taxol expands 1{beta}4 but not 1{beta}3 lattices. Kinesin-driven microtubule gliding detects this conformational shift - 1{beta}4 microtubules glide at ~450 nm/sec in 400 nM taxol, but at ~750 nm/sec in 10 M taxol, whereas 1{beta}3 microtubules glide at ~450 nm/sec, even in 10 M taxol. Thus, taxol readily stabilises 1{beta}4 GDP-tubulin lattices and shifts them to a fastgliding conformation, but stabilises 1{beta}3 lattices much less readily and without shifting their conformation. These isotype-specific actions of taxol may drive the switch to {beta}3 tubulin commonly seen in taxol-resistant tumours.