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J. Biol. Chem., Vol. 275, Issue 39, 30335-30343, September 29, 2000
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From the Max-Planck-Unit for Structural Molecular Biology c/o DESY,
Notkestrasse 85, D-22607 Hamburg, Germany
Tau protein modulates microtubule dynamics and
forms insoluble aggregates in Alzheimer's disease. Because there is a
discrepancy between reported affinities of Tau to microtubules, we
determined the interaction over a wide concentration range using a
sensitive enzyme-linked immunosorbent assay. We found that the
interaction is biphasic and not monophasic as assumed earlier. The
first binding phase is typical for identical and noninteracting binding
sites, with dissociation constants around 0.1 µM
and stoichiometries around 0.2 Tau/tubulin dimer. Surprisingly, the
second phase is nonsaturable and shows a nearly linear increase in
bound Tau versus free Tau for free Tau concentrations
higher than 2 µM. The slope is proportional to the
microtubule concentration. From this we define an overloading parameter
with values around 50 µM. The influence of Tau isoform,
phosphorylation, and dimerization on both phases was investigated.
Remarkably the overloading of Tau on microtubules leads to a thioflavin
S fluorescence increase reminiscent of that seen with Tau aggregated
into Alzheimer paired helical filaments. Because polyanions stimulate
Tau aggregation and because the C-terminal domain of tubulin is
polyanionic, we suggest that an early conformational change in Tau
leading to paired helical filament aggregation occurs right on the
microtubule surface.
Nonsaturable Binding Indicates Clustering of Tau on the
Microtubule Surface in a Paired Helical Filament-like Conformation*
,
*
This work was supported by the Deutsche
Forschungsgemeinschaft.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
This work was done in part as a doctoral thesis.
§
To whom correspondence should be addressed. Tel.: 49-40-89982810;
Fax: 49-40-89716822; E-mail: mand@mpasmb.desy.de.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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