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

Hyperphosphorylated forms of the neuronal microtubule (MT)-associated prote in tau are major components of Alzheimer's disease paired helical filaments . Previously, we reported that AB alpha C, the dominant brain isoform of pr otein phosphatase 2A (PP2A), is localized on MTs, binds directly to tau, an d is a major tau phosphatase in cells. We now describe direct interactions among tau, PP2A, and MTs at the submolecular level. Using tau deletion muta nts, we found that ABaC binds a domain on tau that is indistinguishable fro m its MI-binding domain. AB alpha C binds directly to MTs through a site th at encompasses its catalytic subunit and is distinct from its binding site for tau, and AB alpha C and tau bind to different domains on MTs. Specific PP2A isoforms bind to MTs with distinct affinities in vitro, and these inte ractions differentially inhibit the ability of PP2A to dephosphorylate vari ous substrates, including tau and tubulin. Finally, tubulin assembly decrea ses PP2A activity in vitro, suggesting that PP2A activity can be modulated by MT dynamics in vivo, Taken together, these findings indicate how structu ral interactions among AB alpha C, tau, and MTs might control the phosphory lation state of tau. Disruption of these normal interactions could contribu te significantly to development of tauopathies such as Alzheimer's disease.