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J Biol Chem, Vol. 274, Issue 36, 25490-25498, September 3, 1999
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From the Departments of Hyperphosphorylated forms of the neuronal
microtubule (MT)-associated protein tau are major components of
Alzheimer's disease paired helical filaments. Previously, we reported
that AB Pathology,
¶ Pharmacology, and ¶¶ Cell Biology and Neuroscience
and the Hamon Center for Therapeutic
Oncologic Research, University of Texas Southwestern Medical
Center, Dallas, Texas 75235-9073, the Department of Internal
Medicine, University of Iowa, Iowa City, Iowa 52242, the
** Department of Neurobiology, University of Heidelberg, D-69120
Heidelberg, Germany, and the §§ Department
of Medical Biochemistry, Ohio State University,
Columbus, Ohio 43210
C, the dominant brain isoform of protein phosphatase 2A
(PP2A), is localized on MTs, binds directly to tau, and is a major tau
phosphatase in cells. We now describe direct interactions among tau,
PP2A, and MTs at the submolecular level. Using tau deletion mutants, we
found that ABC binds a domain on tau that is indistinguishable from
its MT-binding domain. ABC binds directly to MTs through a site that
encompasses its catalytic subunit and is distinct from its binding site
for tau, and ABC and tau bind to different domains on MTs. Specific
PP2A isoforms bind to MTs with distinct affinities in
vitro, and these interactions differentially inhibit the ability
of PP2A to dephosphorylate various substrates, including tau and
tubulin. Finally, tubulin assembly decreases PP2A activity in
vitro, suggesting that PP2A activity can be modulated by MT dynamics in vivo. Taken together, these findings indicate
how structural interactions among ABC, tau, and MTs might control the phosphorylation state of tau. Disruption of these normal
interactions could contribute significantly to development of
tauopathies such as Alzheimer's disease.
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