Understanding tubulin - Taxol interactions: Mutations that impart Taxol binding to yeast tubulin

Mohan L. Gupta, Claudia J. Bode, Gunda I. Georg, Richard H. Himes

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

We have successfully used mutagenesis to engineer Taxol (paclitaxel) binding activity in Saccharomyces cerevisiae tubulin. Taxol, a successful antitumor agent, acts by promoting tubulin assembly and stabilizing microtubules. Several structurally diverse antimitotic compounds, including the epothilones, compete with Taxol for binding to mammalian microtubules, suggesting that Taxol and these compounds share an overlapping binding site. However, Taxol has no effect on tubulin or microtubules from S. cerevisiae, whereas epothilone does. After considering data on Taxol binding to mammalian tubulin and recent modeling studies, we have hypothesized that differences in five key amino acids are responsible for the lack of Taxol binding to yeast tubulin. After changing these amino acids to those found in mammalian brain tubulin, we observed Taxol-related activity in yeast tubulin comparable to that in mammalian tubulin. Importantly, this experimental system can be used to reveal tubulin interactions with Taxol, the epothilones, and other Taxol-like compounds.

Original languageEnglish (US)
Pages (from-to)6394-6397
Number of pages4
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number11
DOIs
StatePublished - May 27 2003

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