open access publication

Article, 2024

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

In: Nature, ISSN 0028-0836, 1476-4687, Volume 625, 7993, Pages 195-203, 10.1038/s41586-023-06870-3

Contributors (10)

Padi S.K.R. [1] Vos M.R. [1] Godek R.J. [1] Fuller J.R. (0000-0002-9029-0923) Kruse T. (0000-0002-2619-7388) [2] Hein J.B. [2] Nilsson J. (0000-0003-4100-1125) [2] Kelker M.S. (0000-0001-8908-2767) Page R. (0000-0002-4645-1232) (Corresponding author) [1] Peti W. (0000-0002-8830-6594) (Corresponding author) [1]

Affiliations

  1. [1] University of Connecticut Health Center
  2. [NORA names: United States; America, North; OECD]
  3. [2] University of Copenhagen
  4. [NORA names: KU University of Copenhagen; University; Denmark; Europe, EU; Nordic; OECD]

Abstract

Progression through the cell cycle is controlled by regulated and abrupt changes in phosphorylation. Mitotic entry is initiated by increased phosphorylation of mitotic proteins, a process driven by kinases, whereas mitotic exit is achieved by counteracting dephosphorylation, a process driven by phosphatases, especially PP2A:B55. 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. Inhibition of PP2A:B55 is achieved by the intrinsically disordered proteins ARPP19 and FAM122A. 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.

Funders

  • Simons Foundation
  • Biological and Environmental Research
  • National Institute of Neurological Disorders and Stroke
  • Novo Nordisk Fonden
  • National Institutes of Health
  • National Institute of General Medical Sciences
  • Office of Science
  • Palmerston North City Council