Molecular Mechanism of PP2A/B55α Phosphatase Inhibition by IER5

Abstract

PP2A serine/threonine phosphatases are heterotrimeric complexes that execute many essential physiologic functions. These activities are modulated by additional regulatory proteins, such as ARPP19, FAM122A, and IER5. Here, we report the cryoelectron microscopy structure of a complex of PP2A/B55 with the N-terminal structured region of IER5 (IER5-N50), which occludes a surface on B55 used for substrate recruitment, and show that IER5-N50 inhibits PP2A/B55 catalyzed dephosphorylation of pTau in biochemical assays. Mutations of full-length IER5 that disrupt its PP2A/B55 interface interfere with co-immunoprecipitation of PP2A/B55. These mutations and deletions that remove the nuclear localization sequence of IER5 suppress cellular events such as KRT1 expression that depend on association of IER5 with PP2A/B55. Querying the Alphafold2 predicted structure database identified SERTA domain proteins as high-confidence PP2A/B55-binding structural homologs of IER5-N50. These studies define the molecular basis of PP2A/B55 inhibition by IER5-family proteins and suggest a roadmap for selective pharmacologic modulation of PP2A/B55 complexes.