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

AbstractProtein 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 interactionsI2PP2Aphysically interactswithPP2A-C by anti tag coimmunoprecipitation(view interaction1,2)I2PP2Aphysically interactswithPP2A-C by pull down(view interaction1,2)PP2A-Aphysically interactswithPP2A-B and PP2A-C by pull down(view interaction