科研之友
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摘要
Tubulin being the fundamental unit of microtubule is actively involved in cell division, transportation and chromosomal segregation. Through this study we tried to investigate the significance of eight residual insert (TVVPGGDL) in S-loop region of alpha-tubulin which is absent in the S-loop of beta-tubulin. This study reports hydrogen bonding interactions between the S-loop and the M-loop in alpha-tubulin whereas salt bridge is observed between S-loop and the H1-S2 loop of beta-tubulin. These residual interactions clearly explain the flexibility/rigidness of the H1-S2 and M loops in alpha and beta subunits which are actively involved in lateral interactions. An increase in bulky residues in the H1-S2 loop along with their interactions with S-loop was found to be responsible for restricted mobility of the H1-S2 loop in beta-subunits. This constraint of the H1-S2 loop in association with S-loop brings in weak lateral interaction between beta-beta subunits in comparison with alpha-alpha subunit interaction.
Next, the available drug resistant mutant from human beta-tubulin protein was investigated using Amino Acid Substitution tools (AAS) like PANTHER, I-Mutant2.0 and Polyphen2. Generated report confirms only the residual mutants at the functionally significant positions like H1-S2 loop, helix H5, T6 loop, B7, B7-H9 loop, H9-B8, H10-B9 and helix H12 to be deleterious. Thus our finding explains the significance of eight residual insert in alpha-subunit which assist in better lateral interaction through their residual contact with M-loop and the role of residual substitution in drug resistance in beta-tubulin. Here we hypothesize that the flexibility of the H1-S2 loop in association with the S-loop determines the strength of lateral interactions. Thus the better understanding of the flexibility of the tubulin protein and residual interactions could assist in better drug designing against cancer.
- 出版日期2013-8
