| PP2A Protein | |
|---|---|
| Protein Name | PP2A |
| Gene | [PPP2CA](/genes/ppp2ca) |
| UniProt ID | P67775 |
| PDB Structure | 3DW8, 4X7W |
| Molecular Weight | ~36 kDa (catalytic subunit) |
| Subcellular Localization | Cytoplasm, nucleus, synapses |
| Protein Family | Ser/Thr protein phosphatase family |
PP2A is a heterotrimeric enzyme consisting of a catalytic subunit (C), a scaffolding subunit (A), and a regulatory subunit (B). The catalytic subunit has a metal-dependent phosphatase domain that coordinates two manganese ions for phosphoester hydrolysis. The structure reveals a conserved active site groove with the signature DXH motif.
PP2A dephosphorylates serine and threonine residues on diverse substrates. In neurons, it regulates synaptic plasticity by controlling AMPA receptor trafficking, regulates tau phosphorylation state, and modulates MAPK signaling. PP2A also controls cell cycle progression and apoptotic pathways.
PP2A activity is decreased in Alzheimer's disease brains, contributing to hyperphosphorylation of tau and NFT formation. PP2A dysregulation is also implicated in Parkinson's disease, where it may affect alpha-synuclein phosphorylation. Reduced PP2A activity impairs synaptic function and contributes to cognitive decline.
Small molecule activators of PP2A (e.g., quinostatin, fingolimod derivatives) are being explored for AD treatment. The goal is to restore PP2A activity to promote tau dephosphorylation and improve synaptic function.