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Effects of Tau and MAP₂ on the Interaction of Maytansine with Tubulin: Inhibitory Effect of Maytansine on Vinblastine-Induced Aggregation of Tubulin¹

Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas 78284

Maytansine, a potent inhibitor of mitosis and in vitro microtubule assembly, was used to demonstrate a striking difference in the mechanism by which two of the main groups of brain microtubule-associated proteins, Tau and MAP₂, interact with tubulin.

At the low concentrations of 0.5 to 2 µM, maytansine inhibited Tau-catalyzed tubulin assembly more effectively than it did MAP₂-catalyzed assembly.

This effect differed markedly from that of vinblastine, although both drugs bind competitively to tubulin. At the same low con centrations, vinblastine almost completely inhibited Tau- and MAP₂-mediated tubulin assembly.

At higher concentrations of 10 to 40 µM, a more striking difference was observed between the actions of the two drugs. Maytansine very effectively inhibited tubulin assembly promoted by either Tau or MAP₂. Vinblastine also had this effect on MAP₂-mediated tubulin assembly but in the presence of Tau induced extensive tubulin aggregation into spirals.

In addition maytansine strongly inhibited vinblastine-induced Tau-dependent tubulin aggregation into spiral polymers. Even at very low concentrations, maytansine completely inhibited the effect of very high concentrations of vinblastine.

These results very strongly suggest that the binding sites of maytansine and vinblastine on the tubulin molecule overlap and that the changes that they probably induce in the conformation of this molecule are markedly different, at least in the presence of microtubule-associated proteins.

¹ This work was supported by Grant AQ726 from the Robert Welch Foundation and by Grant CA26376 from the NIH. Electron microscopy was supported by Grant NS13560 from the NIH to Dr. Leslie Wilson.

² Present address: Unité Thyroide, INSERM, 94270 Bicêtre, France.

³ Present address: Department of Biological Sciences, University of California, Santa Barbara, CA 93206.

⁴ Present address: Department of Obstetric and Gynecology, University of Texas Health Science Center, San Antonio, TX 78294.

Received 4/ 6/84. Revised 3/20/85. Accepted 6/ 5/85.

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