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| Title | Cryo-EM structures of PP2A:B55 with p107 and Eya3 define substrate recruitment. |
|---|---|
| Journal, issue, pages | Nat Struct Mol Biol, Vol. 32, Issue 8, Page 1373-1382, Year 2025 |
| Publish date | Apr 17, 2025 |
Authors | Sathish K R Padi / Rachel J Godek / Wolfgang Peti / Rebecca Page / ![]() |
| PubMed Abstract | 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 ...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 links | Nat Struct Mol Biol / PubMed:40247147 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.6 - 2.7 Å |
| Structure data | EMDB-45243, PDB-9c6b: EMDB-45292, PDB-9c7t: |
| Chemicals | ![]() ChemComp-FE2: ![]() ChemComp-ZN: |
| Source |
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Keywords | HYDROLASE/SUBSTRATE / PP2A:B55 / p107 / substrate complex / HYDROLASE / HYDROLASE-SUBSTRATE complex / Eya3 |
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