Evidence map›Paper›PMID 40209703›Full record

ArticleCell chemical biology2025

Molecular mechanism of PP2A/B55α phosphatase inhibition by IER5.

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

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell chemical biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Article
  2. Fuzziness in enzymatic catalysis.Current opinion in structural biology · 2025
    Review
  3. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

9 authors.

Ruili CaoDepartment of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Daniel T D JonesDepartment of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Li PanDepartment of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
Annie YangDepartment of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Shumei WangDepartment of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
Sathish K R PadiDepartment of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT, USA.
Shaun RawsonDepartment of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Jon C AsterDepartment of Pathology, Brigham and Women's Hospital, Boston, MA, USA. Electronic address: jaster@bwh.harvard.edu.
Stephen C BlacklowDepartment 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. Electronic address: stephen_blacklow@hms.harvard.edu.

Funding

Notch Signaling in CancerR35CA220340 · NCI · HARVARD MEDICAL SCHOOL · PI BLACKLOW, STEPHEN C. · 2017 to 2023
$7.1M
Dynamics of Notch SignalingR01CA272484 · NCI · HARVARD MEDICAL SCHOOL · PI Stephen C. Blacklow · 2022 to 2026
$3.3M
NCI NIH HHS R01 CA272484NCI NIH HHS R35 CA220340
6 · The paper itself

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.

Indexed as

Membrane ProteinsProtein Phosphatase 2Cryoelectron MicroscopyHumansModels, MolecularMembrane ProteinsPPP2R5A protein, humanProtein Phosphatase 2Alphafoldcryoelectron microscopyFoldseekimmediate early response genesKRT1nuclear localizationprotein phosphatase 2Astructure prediction

Identifiers

PMID40209703
PMCPMC12067903

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.