Molecular Mechanism of PP2A/B55α Phosphatase Inhibition by IER5.

Autor:	Cao R; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Jones DT; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Pan L; Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA., Yang A; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Wang S; Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA., Padi SKR; Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT, USA., Rawson S; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Aster JC; Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA., Blacklow SC; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Aug 26. Date of Electronic Publication: 2024 Aug 26.
DOI:	10.1101/2023.08.29.555174
Abstrakt:	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/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. 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/B55α. Querying the Alphafold2 predicted structure database identified SERTA domain proteins as high-confidence PP2A/B55α-binding structural homologs of IER5-N50. These studies define the molecular basis of PP2A/B55α inhibition by IER5-family proteins and suggest a roadmap for selective pharmacologic modulation of PP2A/B55α complexes. Competing Interests: SCB 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. JCA is a consultant for Ayala Pharmaceuticals, Cellestia, Inc., SpringWorks Therapeutics, and Remix Therapeutics. The other authors declare that they have no competing interests.
Databáze:	MEDLINE
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