Molecular interactions among protein phosphatase 2A, tau, and microtubules. Implications for the regulation of tau phosphorylation and the development of tauopathies

Estelle Sontag; Viyada Nunbhakdi-Craig; Gloria Lee; Roland Brandt; C Kamibayashi; Jeffrey Kuret; C L White III; Marc C Mumby; George S Bloom

doi:10.1074/jbc.274.36.25490

Back

Molecular interactions among protein phosphatase 2A, tau, and microtubules. Implications for the regulation of tau phosphorylation and the development of tauopathies

Journal article

Open access

Peer reviewed

Molecular interactions among protein phosphatase 2A, tau, and microtubules. Implications for the regulation of tau phosphorylation and the development of tauopathies

Estelle Sontag, Viyada Nunbhakdi-Craig, Gloria Lee, Roland Brandt, C Kamibayashi, Jeffrey Kuret, C L White III, Marc C Mumby and George S Bloom

The Journal of biological chemistry, Vol.274(36), pp.25490-25498

09/03/1999

DOI: 10.1074/jbc.274.36.25490

PMID: 10464280

Files and links (1)

url

https://doi.org/10.1074/jbc.274.36.25490View

Published (Version of record) Open Access

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 ABalphaC, 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 ABalphaC binds a domain on tau that is indistinguishable from its MT-binding domain. ABalphaC binds directly to MTs through a site that encompasses its catalytic subunit and is distinct from its binding site for tau, and ABalphaC 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 ABalphaC, 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.

Phosphorylation

Microtubules - metabolism

Animals

Neurons - ultrastructure

Cattle

Humans

Phosphoprotein Phosphatases - metabolism

Alzheimer Disease - metabolism

tau Proteins - metabolism

Neurons - metabolism

Protein Phosphatase 2

Details

Title: Subtitle: Molecular interactions among protein phosphatase 2A, tau, and microtubules. Implications for the regulation of tau phosphorylation and the development of tauopathies
Creators: Estelle Sontag - Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9073, USA. Estelle.Sontag@email.swmed.edu
Viyada Nunbhakdi-Craig
Gloria Lee
Roland Brandt
C Kamibayashi
Jeffrey Kuret
C L White III
Marc C Mumby
George S Bloom
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.274(36), pp.25490-25498
DOI: 10.1074/jbc.274.36.25490
PMID: 10464280
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: AG12300 / NIA NIH HHS HL31107 / NHLBI NIH HHS GM49505 / NIGMS NIH HHS
Language: English
Date published: 09/03/1999
Academic Unit: Iowa Neuroscience Institute; Immunology; Internal Medicine
Record Identifier: 9984065394902771

Metrics

21 Record Views

271 Times Cited - Web of Science