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Interaction of microtubule depolymerizing agent indanocine with different human ?? tubulin isotypes.

ABSTRACT: 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 ?? tubulin heterodimer. However, it's precise binding mode, involved molecular interactions and the binding affinities with different ??-tubulin isotypes present in MDR cells are not well understood. Here, the binding affinities of human ??-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 ?I, ?IIa, ?III and ?VI isotypes. However, such differences are not observed in the amino acid sequences of ?IVa, ?IVb, and ?V tubulin isotypes at indanocine binding pockets. Docking and molecular dynamics simulation results show that indanocine prefers the interface binding pocket of ??IIa, ??III, ??IVb, ??V, and ??VI tubulin isotypes; whereas it is expelled from the interface binding pocket of ??IVa and ??I-tubulin isotypes. Further, binding free energy calculations show that ??VI has the highest binding affinity and ??I has the lowest binding affinity for indanocine among all ?-tubulin isotypes. The binding free energy decreases in the order of ??VI > ??IVb > ??IIa > ??III > ??V > ??IVa > ??I. 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.

SUBMITTER: Kumbhar BV

PROVIDER: S-EPMC5870988 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Interaction of microtubule depolymerizing agent indanocine with different human αβ tubulin isotypes.

Kumbhar Bajarang Vasant BV Panda Dulal D Kunwar Ambarish A

PloS one 20180327 3

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 inter ...[more]

PMID: 29584771

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Project description:BackgroundThe multi-tubulin hypothesis proposes that each tubulin isotype performs a unique role, or subset of roles, in the universe of microtubule function(s). To test this hypothesis, we are investigating the functions of the recently discovered, noncanonical β-like tubulins (BLTs) of the ciliate, Tetrahymena thermophila. Tetrahymena forms 17 distinct microtubular structures whose assembly had been thought to be based on single α- and β-isotypes. However, completion of the macronuclear genome sequence of Tetrahymena demonstrated that this ciliate possessed a β-tubulin multigene family: two synonymous genes (BTU1 and BTU2) encode the canonical β-tubulin, BTU2, and six genes (BLT1-6) yield five divergent β-tubulin isotypes. In this report, we examine the structural features and functions of two of the BLTs (BLT1 and BLT4) and compare them to those of BTU2.Methodology/principal findingsWith respect to BTU2, BLT1 and BLT4 had multiple sequence substitutions in their GTP-binding sites, in their interaction surfaces, and in their microtubule-targeting motifs, which together suggest that they have specialized functions. To assess the roles of these tubulins in vivo, we transformed Tetrahymena with expression vectors that direct the synthesis of GFP-tagged versions of the isotypes. We show that GFP-BLT1 and GFP-BLT4 were not detectable in somatic cilia and basal bodies, whereas GFP-BTU2 strongly labeled these structures. During cell division, GFP-BLT1 and GFP-BLT4, but not GFP-BTU2, were incorporated into the microtubule arrays of the macronucleus and into the mitotic apparatus of the micronucleus. GFP-BLT1 also participated in formation of the microtubules of the meiotic apparatus of the micronucleus during conjugation. Partitioning of the isotypes between nuclear and ciliary microtubules was confirmed biochemically.Conclusion/significanceWe conclude that Tetrahymena uses a family of distinct β-tubulin isotypes to construct subsets of functionally different microtubules, a result that provides strong support for the multi-tubulin hypothesis.

Dataset Information

Interaction of microtubule depolymerizing agent indanocine with different human ?? tubulin isotypes.

Publications

Interaction of microtubule depolymerizing agent indanocine with different human αβ tubulin isotypes.

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