Rationalization of paclitaxel insensitivity of yeast β-tubulin and human βIII-tubulin isotype using principal component analysis

The paclitaxel-resistance of human βIII tubulin isotype and yeast β-tubulin uniquely mapped on to the lowest two principal components, defining the paclitaxel-binding site residues of β-tubulin. The molecular mechanisms behind paclitaxel-resistance, mediated through key residues, were identified from structural consequences of characteristic mutations that confer paclitaxel-resistance. Specifically, Ala277 in βIII isotype was shown to be crucial for paclitaxel-resistance.The present analysis captures the origin of two apparently unrelated events, paclitaxel-insensitivity of yeast tubulin and human βIII tubulin isotype, through two common collective sequence vectors.Microtubules are structures composed of polymerized tubulin heterodimers and play fundamental roles in vital cellular processes such as chromosome segregation, intracellular transport and maintenance of cell shape [1]. The major component of microtubules is the hetero-dimeric (αβ) protein tubulin. Mammalian tissues express different α- and β-tubulin isotypes [2] that are known to play specific biological functions, exhibit tissue-restricted expression, possess differential binding affinities for antimitotic agents and exhibit different kinetics and dynamics of microtubule assembly [3-5].Paclitaxel, a product of plant secondary metabolism, binds to the β-tubulin subunit and inhibits microtubule dynamics, thereby blocking cell cycle progression during mitosis at the metaphase/anaphase transition and activating cell death [6-8]. It is an important cancer chemotherapeutic agent for treatment of advanced ovarian, lung and breast carcinoma, and shows promising activity against several other carcinomas [9,10]. Although paclitaxel is currently used in chemotherapy, clinical resistance against paclitaxel can become a significant problem. The human βIII tubulin isotype has been implicated to play a crucial role in conferring paclitaxel resistance. Increased expression of the βIII tubulin isotype inhibits cell proli