title: Rationalization of paclitaxel insensitivity of yeast β-tubulin and human βIII-tubulin isotype using principal component analysis.
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 β-tubulin isotypes, can have profound impact on paclitaxel-tubulin binding. To capture the experimentally observed paclitaxel-resistance of human βIII tubulin isotype and yeast β-tubulin, within a common theoretical framework, we have performed structural principal component analyses of β-tubulin sequences across eukaryotes.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Biophysics, Bose Institute, P-1/12 CIT Scheme VIIM, Kolkata, 70054, India.
authors: Lalita
authors: L
authors: Das
authors: Bhabatarak
authors: B
authors: Bhattacharya
authors: Gautam
authors: G
authors: Basu
mesh_terms: D000409:Alanine / Q000737:chemistry / Q000235:genetics; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017239:Paclitaxel / Q000737:chemistry* / Q000378:metabolism; D010944:Plants / Q000235:genetics; D025341:Principal Component Analysis / Q000379:methods; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D014404:Tubulin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D005656:Fungal Proteins; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D014404:Tubulin; D000409:Alanine; D017239:Paclitaxel