Dataset Information

Taxol acts differently on different tubulin isotypes.

ABSTRACT: Taxol is a small molecule effector that allosterically locks tubulin into the microtubule lattice. We show here that taxol has different effects on different single-isotype microtubule lattices. Using in vitro reconstitution, we demonstrate that single-isotype α1β4 GDP-tubulin lattices are stabilised and expanded by 10 µM taxol, as reported by accelerated microtubule gliding in kinesin motility assays, whereas single-isotype α1β3 GDP-tubulin lattices are stabilised but not expanded. This isotype-specific action of taxol drives gliding of segmented-isotype GDP-taxol microtubules along convoluted, sinusoidal paths, because their expanded α1β4 segments try to glide faster than their compacted α1β3 segments. In GMPCPP, single-isotype α1β3 and α1β4 lattices both show accelerated gliding, indicating that both can in principle be driven to expand. We therefore propose that taxol-induced lattice expansion requires a higher taxol occupancy than taxol-induced stabilisation, and that higher taxol occupancies are accessible to α1β4 but not α1β3 single-isotype lattices.

SUBMITTER: Chew YM

PROVIDER: S-EPMC10505170 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Taxol acts differently on different tubulin isotypes.

Chew Yean Ming YM Cross Robert A RA

Communications biology 20230916 1

Taxol is a small molecule effector that allosterically locks tubulin into the microtubule lattice. We show here that taxol has different effects on different single-isotype microtubule lattices. Using in vitro reconstitution, we demonstrate that single-isotype α1β4 GDP-tubulin lattices are stabilised and expanded by 10 µM taxol, as reported by accelerated microtubule gliding in kinesin motility assays, whereas single-isotype α1β3 GDP-tubulin lattices are stabilised but not expanded. This isotype ...[more]

PMID: 37717119

Similar Datasets

Project description:Tubulin isotypes are known to regulate the stability and dynamics of microtubules, and are also involved in the development of resistance against microtubule-targeted cancer drugs. Indanocine, a potent microtubule depolymerizing agent, is highly active against multidrug-resistant (MDR) cancer cells without affecting normal cells. It is known to disrupt microtubule dynamics in cells and induce apoptotic cell death. Indanocine is reported to bind to tubulin at the colchicine site i.e. at the interface of αβ tubulin heterodimer. However, it's precise binding mode, involved molecular interactions and the binding affinities with different αβ-tubulin isotypes present in MDR cells are not well understood. Here, the binding affinities of human αβ-tubulin isotypes with indanocine were examined, employing the molecular modeling approach i.e. docking, molecular dynamics simulation and binding energy calculations. Multiple sequence analysis suggests that the amino acid sequences are different in the indanocine binding pockets of βI, βIIa, βIII and βVI isotypes. However, such differences are not observed in the amino acid sequences of βIVa, βIVb, and βV tubulin isotypes at indanocine binding pockets. Docking and molecular dynamics simulation results show that indanocine prefers the interface binding pocket of αβIIa, αβIII, αβIVb, αβV, and αβVI tubulin isotypes; whereas it is expelled from the interface binding pocket of αβIVa and αβI-tubulin isotypes. Further, binding free energy calculations show that αβVI has the highest binding affinity and αβI has the lowest binding affinity for indanocine among all β-tubulin isotypes. The binding free energy decreases in the order of αβVI > αβIVb > αβIIa > αβIII > αβV > αβIVa > αβI. Thus, our study provides a significant understanding of involved molecular interactions of indanocine with tubulin isotypes, which may help to design potent indanocine analogues for specific tubulin isotypes in MDR cells in future.

Dataset Information

Taxol acts differently on different tubulin isotypes.

Publications

Taxol acts differently on different tubulin isotypes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets