Molecular Interactions among Protein Phosphatase 2A, Tau, and Microtubules

doi:10.1074/jbc.274.36.25490

Molecular Interactions among Protein Phosphatase 2A, Tau, and Microtubules

IMPLICATIONS FOR THE REGULATION OF TAU PHOSPHORYLATION AND THE DEVELOPMENT OF TAUOPATHIES*

From the Departments of ^‡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

Abstract

Hyperphosphorylated forms of the neuronal microtubule (MT)-associated protein tau are major components of Alzheimer’s disease paired helical filaments. Previously, we reported that ABαC, 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 ABαC binds a domain on tau that is indistinguishable from its MT-binding domain. ABαC binds directly to MTs through a site that encompasses its catalytic subunit and is distinct from its binding site for tau, and ABαC 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 ABαC, 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.

Footnotes

↵* This work was supported by National Institutes of Health Grants AG12300 (to E. S. and C. L. W.), GM49505 and HL31107 (to M. C. M.), AG14452 (to J. K.), and NS30485 (to G. S. B.); by Alzheimer’s Disease and Related Disorders Association Grant IIRG-93-113 (to G. L.); and by Welch Foundation Grant I-1236 (to G. S. B.).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.
↵§ To whom correspondence should be addressed: Dept. of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9073. Tel.: 214-648-2327; Fax: 214-648-2077; E-mail: Estelle.Sontag@email.swmed.edu.
Abbreviations:

MT

microtubule

MAP

microtubule-associated protein

PP2A

protein phosphatase 2A

PP1

protein phosphatase 1

rTau

recombinant tau

PIPES

1,4-piperazinediethanesulfonic acid

MOPS

4-morpholinepropanesulfonic acid

PAGE

polyacryl- amide gel electrophoresis
- Received April 29, 1999.
- Revision received June 16, 1999.
The American Society for Biochemistry and Molecular Biology, Inc.