Differential interaction of tubulin isotypes with the antimitotic compound ikp-104

I. A. Khan, I. Tomita, F. Mizuhashi, R. F. Ludueña

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9 Scopus citations

Abstract

The tubulin molecule is a heterodimer composed of two polypeptide chains, designated α and β; both α and β exist in numerous isotypic forms, which differ in their assembly and drag binding properties. 2-(4-Fluorophenyl)-1-(2-Chloro-3,5-dimethoxyphenyl)-3-methyl-6-ph enyl-4(1H)-pyridinone (IKP-104) is an antimitotic compound which inhibits polymerization and induces depolymerization of microtubules [Mizuhashi, F., et al. (1992) Jpn. J. Cancer Res. 83, 211]. Since the previous work was undertaken with isotypically unfractionated tubulin, we have investigated the interactions of IKP-104 with the isotypically purified tubulin dimers (αβII, (αβIII, and αβIV). We find that IKP-104 binds to αβII and αβIII at two classes of binding sites. However, affinities for each class of site are much weaker for αβIII than for αβII. Interestingly, the low-affinity site on arty was not detectable. Its high-affinity site was weaker than those of either αβII or αβIII. In a pattern consistent with these results, IKP-104 inhibited assembly better with αβII than with the other two dimers. Higher concentrations of IKP-104 induced formation of spiral aggregates from αβII and αβIII but not from αβIV. Our results suggest that the interaction of IKP-104 with tubulin isotypes is very complex: αβII and αβIII differ quantitatively in their interaction with IKP-104, and αβIV's interaction differs brfseq 4oth quantitatively and qualitatively from those of the other two dimers.

Original languageEnglish (US)
Pages (from-to)9001-9009
Number of pages9
JournalBiochemistry
Volume39
Issue number30
DOIs
StatePublished - Aug 1 2000

ASJC Scopus subject areas

  • Biochemistry

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    Khan, I. A., Tomita, I., Mizuhashi, F., & Ludueña, R. F. (2000). Differential interaction of tubulin isotypes with the antimitotic compound ikp-104. Biochemistry, 39(30), 9001-9009. https://doi.org/10.1021/bi000331o