Molecular Mechanism of PP2A/B55α Inhibition by IER5.

PP2A serine/threonine protein phosphatases are heterotrimeric complexes that have a wide range of essential physiologic functions. The B55α form of PP2A has critical roles in cell cycle regulation, mitotic exit, and the DNA damage response 1-6 . Its activity is modulated by additional regulatory proteins, such as ARPP19 7 , FAM122A 8 , and IER5 9 . However, the precise mechanisms underlying the modulation of PP2A activity by these proteins remain elusive. Here, we show that IER5 inhibits pTau dephosphorylation by PP2A/B55α in biochemical assays and report a cryoelectron microscopy structure of the PP2A/B55α-IER5 complex, which reveals that IER5 occludes a surface on B55α used for substrate recruitment 10-12 . Mutation of interface residues on IER5 interferes with recovery of B55α in co-immunoprecipitation assays and suppresses events in squamous carcinoma cells, such as KRT1 expression, that depend on inhibition of PP2A/B55α by IER5 9 . These studies define the molecular basis for PP2A inhibition by IER5 and suggest a roadmap for selective pharmacologic modulation of PP2A/B55α complexes.