KINETIC STABILIZATION OF MICROTUBULE DYNAMICS AT STEADY-STATE BY TAU AND MICROTUBULE-BINDING DOMAINS OF TAU

Tau is a neuronal microtubule-associated protein that plays an importa nt role in stabilizing axonal microtubules and maintaining neuronal pr ocesses. To investigate the mechanisms by which tau performs these fun ctions, we have determined the actions of full-length adult tau and ta u peptides corresponding to two different microtubule-binding domains of tau (the first repeat, R1, VRSKIGSTEN-LKHQPGGG, and the first inter repeat, R1-R2 IR, KYQINNKK) on the growing and shortening dynamics at the plus ends of individual microtubules at steady state. Tau suppress ed steady-state microtubule dynamics at very low molar ratios of tau t o tubulin. At the lowest ratios examined (tau:tubulin ratios of 1:175 and 1:85), suppression of dynamics occurred in the absence of a detect able change in polymer mass. Tau reduced the mean rate and extent of s hortening and, in contrast to previous work carried out under conditio ns of net polymer gain, tau also suppressed the mean rate and extent o f growing. Tau also strongly increased the rescue frequency, it modera tely suppressed the catastrophe frequency and it strongly increased th e percentage of total time that the microtubules spent in an attenuate d (pause) state, neither growing nor shortening detectably. In additio n, both the R1 and R1-R2 IR tau peptides suppressed steady-state micro tubule dynamics in a sequence-specific manner and in a manner that was qualitatively indistinguishable from full-length tau. The data provid e significant support for a mechanism in which the binding of tau to i ndividual tubulin subunits in microtubules induces a conformational ch ange that strengthens inter-tubulin bonding.