Effects of Tau and MAP2 on the interaction of maytansine with tubulin: inhibitory effect of maytansine on vinblastine-induced aggregation of tubulin.
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 microM, 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 concentrations, vinblastine almost completely inhibited Tau- and MAP2-mediated tubulin assembly. At higher concentrations of 10 to 40 microM, 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.
D000818:Animals; D002642:Chick Embryo; D004347:Drug Interactions; D005260:Female; D008453:Maytansine / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000494:pharmacology*; D010078:Oxazines / Q000494:pharmacology*; D011108:Polymers; D014404:Tubulin; D014747:Vinblastine / Q000494:pharmacology*; D016875:tau Proteins
D008869:Microtubule-Associated Proteins; D010078:Oxazines; D011108:Polymers; D014404:Tubulin; D016875:tau Proteins; D008453:Maytansine; D014747:Vinblastine