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TitleCryo-EM structures of PP2A:B55 with p107 and Eya3 define substrate recruitment.
Journal, issue, pagesNat Struct Mol Biol, Vol. 32, Issue 8, Page 1373-1382, Year 2025
Publish dateApr 17, 2025
AuthorsSathish K R Padi / Rachel J Godek / Wolfgang Peti / Rebecca Page /
PubMed AbstractPhosphoprotein phosphatases (PPPs) achieve specificity by binding substrates and regulators using PPP-specific short motifs. Protein phosphatase 2A (PP2A) is a highly conserved phosphatase that ...Phosphoprotein phosphatases (PPPs) achieve specificity by binding substrates and regulators using PPP-specific short motifs. Protein phosphatase 2A (PP2A) is a highly conserved phosphatase that regulates cell signaling and is a tumor suppressor. Here, we use cryo-electron microscopy and nuclear magnetic resonance (NMR) spectroscopy to investigate the mechanisms of human p107 substrate and Eya3 regulator recruitment to the PP2A:B55 holoenzyme. We show that, while they associate with B55 using a common set of interaction pockets, the mechanism of substrate and regulator binding differs and is distinct from that observed for PP2A:B56 and other PPPs. We also identify the core B55 recruitment motif in Eya3 proteins, a sequence conserved amongst the Eya family. Lastly, using NMR-based dephosphorylation assays, we demonstrate how B55 recruitment directs PP2A:B55 fidelity through the selective dephosphorylation of specific phosphosites. As PP2A:B55 orchestrates mitosis and DNA damage repair, these data provide a roadmap for pursuing new avenues to therapeutically target this complex by individually blocking a subset of regulators that use different B55 interaction sites.
External linksNat Struct Mol Biol / PubMed:40247147 / PubMed Central
MethodsEM (single particle)
Resolution2.6 - 2.7 Å
Structure data

EMDB-45243, PDB-9c6b:
PP2A:B55-p107 substrate complex
Method: EM (single particle) / Resolution: 2.6 Å

EMDB-45292, PDB-9c7t:
PP2A:B55-Eya3 substrate complex
Method: EM (single particle) / Resolution: 2.7 Å

Chemicals

ChemComp-FE2:
Unknown entry

ChemComp-ZN:
Unknown entry

Source
  • homo sapiens (human)
KeywordsHYDROLASE/SUBSTRATE / PP2A:B55 / p107 / substrate complex / HYDROLASE / HYDROLASE-SUBSTRATE complex / Eya3

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