IKP104-induced decay of tubulin: Role of the a-ring binding site of colchicine

Asish R. Chaudhuri, Isao Tomita, Fukutaro Mizuhashi, Kyoji Murata, James L. Potenziano, Richard F. Ludueña

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Tubulin, the major subunit protein of microtubules, has a tendency to lose its ability to assemble or to interact with ligands in a time-dependent process known as decay. Decay involves the increase in exposure of sulfhydryl groups and hydrophobic areas. The antimitotic drug IKP104 [2-(4- fluorophenyl)-1-(2-chloro-3,5-dimethoxyphenyl)-3-methyl-6-phenyl-4(1H)- pyridinone] accelerates the decay of tubulin [Luduena et al. (1995) Biochemistry 34, 15751-15759]. In the presence of colchicine, however, IKP 104 stabilizes tubulin against decay. We have shown that the stability and the acceleration of the decay of tubulin are mediated respectively by the high- and low-affinity binding site(s) of IKP104 [Chaudhuri et al. (1998) J. Protein Chem. 17, 303-309]. To better understand the mechanism by which colchicine protects tubulin from IKP104-induced decay, we examined the effect of colchicine and its analogues on this process. We found that IKP104 unfolds tubulin in a process involving a specific domain where colchicine interacts, although the binding sites of these two drugs are distinctly different. 2- Methoxy-5(2',3',4'-trimethoxyphenyl) tropolone (MTPT), the bicyclic analogue of colchicine that lacks the B-ring, can also protect tubulin from IKP104- induced decay. An A-ring analogue of colchicine, 3,4,5-trimethoxybenzaldehyde (TMB), can also stop IKP104-induced unfolding of tubulin significantly. Interestingly, the C-ring analogue of colchicine, tropolone methyl ether (TME), does not prevent this process. Our results thus suggest that neither the B-ring nor the C-ring binding regions of colchicine are involved in the IKP104-induced decay and that the A-ring binding site of colchicine on tubulin plays a crucial role in IKP104-induced decay.

Original languageEnglish (US)
Pages (from-to)17157-17162
Number of pages6
JournalBiochemistry
Volume37
Issue number49
DOIs
StatePublished - Dec 8 1998

ASJC Scopus subject areas

  • Biochemistry

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