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

Mol Cell. 2008 Sep 26;31(6):873-85. doi: 10.1016/j.molcel.2008.08.006.


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 Balpha. We show that Balpha specifically and markedly facilitates dephosphorylation of the phosphorylated Tau in our reconstituted assay. The Balpha subunit comprises a seven-bladed beta propeller, with an acidic, substrate-binding groove located in the center of the propeller. The beta propeller latches onto the ridge of the PP2A scaffold subunit with the help of a protruding beta hairpin arm. Structure-guided mutagenesis studies revealed the underpinnings of PP2A-mediated dephosphorylation of Tau.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Crystallography, X-Ray
  • Holoenzymes / chemistry
  • Models, Molecular
  • Molecular Sequence Data
  • Peptide Fragments / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Phosphatase 2 / chemistry*
  • Protein Subunits / metabolism*
  • Recombinant Proteins / metabolism
  • tau Proteins / metabolism*


  • Holoenzymes
  • Peptide Fragments
  • Protein Subunits
  • Recombinant Proteins
  • tau Proteins
  • Protein Phosphatase 2

Associated data

  • PDB/3DW8