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

Sathish K. R. Padi, Margaret R. Vos, Rachel J. Godek, James R. Fuller, Thomas Kruse, Jamin B. Hein, Jakob Nilsson, Matthew S. Kelker, Rebecca Page () and Wolfgang Peti ()
Additional contact information
Sathish K. R. Padi: University of Connecticut Health Center
Margaret R. Vos: University of Connecticut Health Center
Rachel J. Godek: University of Connecticut Health Center
James R. Fuller: Helix Biostructures
Thomas Kruse: University of Copenhagen
Jamin B. Hein: University of Copenhagen
Jakob Nilsson: University of Copenhagen
Matthew S. Kelker: Helix Biostructures
Rebecca Page: University of Connecticut Health Center
Wolfgang Peti: University of Connecticut Health Center

Nature, 2024, vol. 625, issue 7993, 195-203

Abstract: Abstract Progression through the cell cycle is controlled by regulated and abrupt changes in phosphorylation1. Mitotic entry is initiated by increased phosphorylation of mitotic proteins, a process driven by kinases2, whereas mitotic exit is achieved by counteracting dephosphorylation, a process driven by phosphatases, especially PP2A:B553. 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 inhibited4. Inhibition of PP2A:B55 is achieved by the intrinsically disordered proteins ARPP195,6 and FAM122A7. 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.

Date: 2024
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-023-06870-3 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:625:y:2024:i:7993:d:10.1038_s41586-023-06870-3

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-023-06870-3

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().