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. 2025 Apr 17;32(4):631-642.e7.
doi: 10.1016/j.chembiol.2025.03.004. Epub 2025 Apr 9.

Molecular mechanism of PP2A/B55α phosphatase inhibition by IER5

Ruili Cao  1 , Daniel T D Jones  1 , Li Pan  2 , Annie Yang  1 , Shumei Wang  2 , Sathish K R Padi  3 , Shaun Rawson  1 , Jon C Aster  4 , Stephen C Blacklow  5
Affiliations

Molecular mechanism of PP2A/B55α phosphatase inhibition by IER5

Ruili Cao et al. Cell Chem Biol. .

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 (cryo-EM) structure of a complex of PP2A/B55α with the N-terminal structured region of IER5 (IER5-N50), which occludes a surface on B55α used for substrate recruitment, and show that IER5-N50 inhibits PP2A/B55α catalyzed dephosphorylation of pTau in biochemical assays. Mutations of full-length IER5 that disrupt its PP2A/B55α interface interfere with co-immunoprecipitation of PP2A/B55α. IER5 antagonism of B55α 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/B55α nuclear inhibition by IER5 and suggest a roadmap for selective pharmacologic modulation of PP2A/B55α complexes.

Keywords: Alphafold; Foldseek; KRT1; cryoelectron microscopy; immediate early response genes; nuclear localization; protein phosphatase 2A; structure prediction.

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Conflict of interest statement

Declaration of interests S.C.B. is on the board of directors of the non-profit Institute for Protein Innovation and the Revson Foundation; is on the scientific advisory board for and receives funding from Erasca, Inc. for an unrelated project; is an advisor to MPM Capital; and is a consultant for IFM, Scorpion Therapeutics, Odyssey Therapeutics, Droia Ventures, and Ayala Pharmaceuticals for unrelated projects. J.C.A. is a consultant for Ayala Pharmaceuticals, Cellestia, Inc., SpringWorks Therapeutics, and Remix Therapeutics.

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