Rationalization of paclitaxel insensitivity of yeast ?-tubulin and human ?III-tubulin isotype using principal component analysis.
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ABSTRACT: BACKGROUND: The chemotherapeutic agent paclitaxel arrests cell division by binding to the hetero-dimeric protein tubulin. Subtle differences in tubulin sequences, across eukaryotes and among ?-tubulin isotypes, can have profound impact on paclitaxel-tubulin binding. To capture the experimentally observed paclitaxel-resistance of human ?III tubulin isotype and yeast ?-tubulin, within a common theoretical framework, we have performed structural principal component analyses of ?-tubulin sequences across eukaryotes. RESULTS: The paclitaxel-resistance of human ?III tubulin isotype and yeast ?-tubulin uniquely mapped on to the lowest two principal components, defining the paclitaxel-binding site residues of ?-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 ?III isotype was shown to be crucial for paclitaxel-resistance. CONCLUSIONS: The present analysis captures the origin of two apparently unrelated events, paclitaxel-insensitivity of yeast tubulin and human ?III tubulin isotype, through two common collective sequence vectors.
SUBMITTER: Das L
PROVIDER: S-EPMC3477043 | biostudies-literature | 2012
REPOSITORIES: biostudies-literature
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