Cryo-EM structures of PP2A:B55–FAM122A and PP2A:B55–ARPP19

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Cryo-EM structures of PP2A:B55–FAM122A and PP2A:B55–ARPP19. / Padi, Sathish K.R.; Vos, Margaret R.; Godek, Rachel J.; Fuller, James R.; Kruse, Thomas; Hein, Jamin B.; Nilsson, Jakob; Kelker, Matthew S.; Page, Rebecca; Peti, Wolfgang.

In: Nature, Vol. 625, No. 7993, 2024, p. 195-203.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Padi, SKR, Vos, MR, Godek, RJ, Fuller, JR, Kruse, T, Hein, JB, Nilsson, J, Kelker, MS, Page, R & Peti, W 2024, 'Cryo-EM structures of PP2A:B55–FAM122A and PP2A:B55–ARPP19', Nature, vol. 625, no. 7993, pp. 195-203. https://doi.org/10.1038/s41586-023-06870-3

APA

Padi, S. K. R., Vos, M. R., Godek, R. J., Fuller, J. R., Kruse, T., Hein, J. B., Nilsson, J., Kelker, M. S., Page, R., & Peti, W. (2024). Cryo-EM structures of PP2A:B55–FAM122A and PP2A:B55–ARPP19. Nature, 625(7993), 195-203. https://doi.org/10.1038/s41586-023-06870-3

Vancouver

Padi SKR, Vos MR, Godek RJ, Fuller JR, Kruse T, Hein JB et al. Cryo-EM structures of PP2A:B55–FAM122A and PP2A:B55–ARPP19. Nature. 2024;625(7993):195-203. https://doi.org/10.1038/s41586-023-06870-3

Author

Padi, Sathish K.R. ; Vos, Margaret R. ; Godek, Rachel J. ; Fuller, James R. ; Kruse, Thomas ; Hein, Jamin B. ; Nilsson, Jakob ; Kelker, Matthew S. ; Page, Rebecca ; Peti, Wolfgang. / Cryo-EM structures of PP2A:B55–FAM122A and PP2A:B55–ARPP19. In: Nature. 2024 ; Vol. 625, No. 7993. pp. 195-203.

Bibtex

@article{72b6ffb3d71a41fdaad5776654f72a74,
title = "Cryo-EM structures of PP2A:B55–FAM122A and PP2A:B55–ARPP19",
abstract = "Progression through the cell cycle is controlled by regulated and abrupt changes in phosphorylation 1. Mitotic entry is initiated by increased phosphorylation of mitotic proteins, a process driven by kinases 2, whereas mitotic exit is achieved by counteracting dephosphorylation, a process driven by phosphatases, especially PP2A:B55 3. Although the role of kinases in mitotic entry is well established, recent data have shown that mitosis is only successfully initiated when the counterbalancing phosphatases are also inhibited 4. Inhibition of PP2A:B55 is achieved by the intrinsically disordered proteins ARPP19 5,6 and FAM122A 7. Despite their critical roles in mitosis, the mechanisms by which they achieve PP2A:B55 inhibition is unknown. Here, we report the single-particle cryo-electron microscopy structures of PP2A:B55 bound to phosphorylated ARPP19 and FAM122A. Consistent with our complementary NMR spectroscopy studies, both intrinsically disordered proteins bind PP2A:B55, but do so in highly distinct manners, leveraging multiple distinct binding sites on B55. Our extensive structural, biophysical and biochemical data explain how substrates and inhibitors are recruited to PP2A:B55 and provide a molecular roadmap for the development of therapeutic interventions for PP2A:B55-related diseases.",
author = "Padi, {Sathish K.R.} and Vos, {Margaret R.} and Godek, {Rachel J.} and Fuller, {James R.} and Thomas Kruse and Hein, {Jamin B.} and Jakob Nilsson and Kelker, {Matthew S.} and Rebecca Page and Wolfgang Peti",
note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2024",
doi = "10.1038/s41586-023-06870-3",
language = "English",
volume = "625",
pages = "195--203",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "nature publishing group",
number = "7993",

}

RIS

TY - JOUR

T1 - Cryo-EM structures of PP2A:B55–FAM122A and PP2A:B55–ARPP19

AU - Padi, Sathish K.R.

AU - Vos, Margaret R.

AU - Godek, Rachel J.

AU - Fuller, James R.

AU - Kruse, Thomas

AU - Hein, Jamin B.

AU - Nilsson, Jakob

AU - Kelker, Matthew S.

AU - Page, Rebecca

AU - Peti, Wolfgang

N1 - Publisher Copyright: © 2023, The Author(s).

PY - 2024

Y1 - 2024

N2 - Progression through the cell cycle is controlled by regulated and abrupt changes in phosphorylation 1. Mitotic entry is initiated by increased phosphorylation of mitotic proteins, a process driven by kinases 2, whereas mitotic exit is achieved by counteracting dephosphorylation, a process driven by phosphatases, especially PP2A:B55 3. Although the role of kinases in mitotic entry is well established, recent data have shown that mitosis is only successfully initiated when the counterbalancing phosphatases are also inhibited 4. Inhibition of PP2A:B55 is achieved by the intrinsically disordered proteins ARPP19 5,6 and FAM122A 7. Despite their critical roles in mitosis, the mechanisms by which they achieve PP2A:B55 inhibition is unknown. Here, we report the single-particle cryo-electron microscopy structures of PP2A:B55 bound to phosphorylated ARPP19 and FAM122A. Consistent with our complementary NMR spectroscopy studies, both intrinsically disordered proteins bind PP2A:B55, but do so in highly distinct manners, leveraging multiple distinct binding sites on B55. Our extensive structural, biophysical and biochemical data explain how substrates and inhibitors are recruited to PP2A:B55 and provide a molecular roadmap for the development of therapeutic interventions for PP2A:B55-related diseases.

AB - Progression through the cell cycle is controlled by regulated and abrupt changes in phosphorylation 1. Mitotic entry is initiated by increased phosphorylation of mitotic proteins, a process driven by kinases 2, whereas mitotic exit is achieved by counteracting dephosphorylation, a process driven by phosphatases, especially PP2A:B55 3. Although the role of kinases in mitotic entry is well established, recent data have shown that mitosis is only successfully initiated when the counterbalancing phosphatases are also inhibited 4. Inhibition of PP2A:B55 is achieved by the intrinsically disordered proteins ARPP19 5,6 and FAM122A 7. Despite their critical roles in mitosis, the mechanisms by which they achieve PP2A:B55 inhibition is unknown. Here, we report the single-particle cryo-electron microscopy structures of PP2A:B55 bound to phosphorylated ARPP19 and FAM122A. Consistent with our complementary NMR spectroscopy studies, both intrinsically disordered proteins bind PP2A:B55, but do so in highly distinct manners, leveraging multiple distinct binding sites on B55. Our extensive structural, biophysical and biochemical data explain how substrates and inhibitors are recruited to PP2A:B55 and provide a molecular roadmap for the development of therapeutic interventions for PP2A:B55-related diseases.

U2 - 10.1038/s41586-023-06870-3

DO - 10.1038/s41586-023-06870-3

M3 - Journal article

C2 - 38123684

AN - SCOPUS:85180251553

VL - 625

SP - 195

EP - 203

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 7993

ER -

ID: 378811540