[PDF][PDF] Structure of a protein phosphatase 2A holoenzyme: insights into B55-mediated Tau dephosphorylation

Y Xu, Y Chen, P Zhang, PD Jeffrey, Y Shi - Molecular cell, 2008 - cell.com
Y Xu, Y Chen, P Zhang, PD Jeffrey, Y Shi
Molecular cell, 2008cell.com
Summary Protein phosphatase 2A (PP2A) regulates many essential aspects of cellular
physiology. Members of the regulatory B/B55/PR55 family are thought to play a key role in
the dephosphorylation of Tau, whose hyperphosphorylation contributes to Alzheimer's
disease. The underlying mechanisms of the PP2A-Tau connection remain largely enigmatic.
Here, we report the complete reconstitution of a Tau dephosphorylation assay and the
crystal structure of a heterotrimeric PP2A holoenzyme involving the regulatory subunit Bα …
Summary
Protein phosphatase 2A (PP2A) regulates many essential aspects of cellular physiology. Members of the regulatory B/B55/PR55 family are thought to play a key role in the dephosphorylation of Tau, whose hyperphosphorylation contributes to Alzheimer's disease. The underlying mechanisms of the PP2A-Tau connection remain largely enigmatic. Here, we report the complete reconstitution of a Tau dephosphorylation assay and the crystal structure of a heterotrimeric PP2A holoenzyme involving the regulatory subunit Bα. We show that Bα specifically and markedly facilitates dephosphorylation of the phosphorylated Tau in our reconstituted assay. The Bα subunit comprises a seven-bladed β propeller, with an acidic, substrate-binding groove located in the center of the propeller. The β propeller latches onto the ridge of the PP2A scaffold subunit with the help of a protruding β hairpin arm. Structure-guided mutagenesis studies revealed the underpinnings of PP2A-mediated dephosphorylation of Tau.
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