Mechanism of inhibition of PP2A activity and abnormal hyperphosphorylation of tau by I2PP2A/SET

Protein phosphatase-2A (PP2A) activity, which is compromised in Alzheimer disease brain, is regulated by two endogenous inhibitors, one of them being I2PP2A, a 277 amino acid long protein also known as SET. Here we report that both the amino terminal fragment (I2NTF; aa 1–175) and the carboxy terminal fragment (I2CTF; aa 176–277) of I2PP2A inhibit PP2A by binding to its catalytic subunit PP2Ac and cause hyperphosphorylation of tau. The C-terminal acidic region in I2CTF and Val 92 in I2NTF are essential for their association with PP2Ac and inhibition of the phosphatase activity.Structured summary of protein interactionsI2PP2A physically interacts with PP2A-C by anti tag coimmunoprecipitation (view interaction 1, 2)I2PP2A physically interacts with PP2A-C by pull down (view interaction 1, 2)PP2A-A physically interacts with PP2A-B and PP2A-C by pull down (view interaction)

► Molecular mechanism of regulation of PP2A activity by I2PP2A/SET.
► Both N- (I2NTF) and C-terminal (I2CTF) fragments of I2PP2A inhibit PP2A activity.
► I2NTF and I2CTF lead to tau hyperphosphorylation by inhibiting PP2A.
► I2CTF binds to PP2Ac and inhibits PP2A activity by its C-terminal acidic region.
► Val-92 in I2NTF is required for its binding to PP2Ac and inhibiting PP2A activity.