TY - JOUR
T1 - Molecular interactions among protein phosphatase 2A, tau, and microtubules. Implications for the regulation of tau phosphorylation and the development of tauopathies
AU - Sontag, Estelle
AU - Nunbhakdi-Craig, Viyada
AU - Lee, Gloria
AU - Brandt, Roland
AU - Kamibayashi, Craig
AU - Kuret, Jeffrey
AU - White, Charles L.
AU - Mumby, Marc C.
AU - Bloom, George S.
PY - 1999/9/3
Y1 - 1999/9/3
N2 - 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 Mrs. 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.
AB - 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 Mrs. 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.
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U2 - 10.1074/jbc.274.36.25490
DO - 10.1074/jbc.274.36.25490
M3 - Article
C2 - 10464280
AN - SCOPUS:0033520355
SN - 0021-9258
VL - 274
SP - 25490
EP - 25498
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 36
ER -