Abstact

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 (cryo-EM) structure of a complex of PP2A/B55alpha with the N-terminal structured region of IER5 (IER5-N50), which occludes a surface on B55alpha used for substrate recruitment, and show that IER5-N50 inhibits PP2A/B55alpha catalyzed dephosphorylation of pTau in biochemical assays. Mutations of full-length IER5 that disrupt its PP2A/B55alpha interface interfere with co-immunoprecipitation of PP2A/B55alpha. IER5 antagonism of B55alpha in keratinocytes is required for expression of KRT1, a differentiation marker. Mini-IER5 composed of IER5-N50 and a nuclear localization sequence restores this activity in IER5 knockout cells. Using structural bioinformatics, we identify homology of IER5-N50 with SERTA (SEI-1, RBT-1, and TARA) domain containing proteins. These studies define the molecular basis of PP2A/B55alpha nuclear inhibition by IER5 and suggest a roadmap for selective pharmacologic modulation of PP2A/B55alpha complexes.