Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jul 15:S0969-2126(25)00248-5.
doi: 10.1016/j.str.2025.06.013. Online ahead of print.

Regulatory mechanisms of PP2A complex assembly driven by physicochemical differences in A-subunit isoforms

Alexander Day  1 , Wei Huang  1 , Daniel Leonard  2 , Caitlin M O'Connor  3 , Goutham Narla  3 , Derek J Taylor  4
Affiliations

Regulatory mechanisms of PP2A complex assembly driven by physicochemical differences in A-subunit isoforms

Alexander Day et al. Structure. .

Abstract

Protein phosphatase 2A (PP2A) is crucial for regulating cellular pathways, with its holoenzyme assembly affecting enzyme function and substrate selection. The PP2A holoenzyme comprises scaffold A-, regulatory B-, and catalytic C-subunits, each with various isoforms. Here, we examine structural and biochemical characteristics of the A-subunit isoforms (Aα and Aβ) and identify different biophysical properties that may promote distinct PP2A functions. Our molecular dynamics simulations and cryo-EM analyses define structural differences in the isoforms that reside primarily at the N-terminus of the A-subunit where it interfaces with regulatory B-subunits. Kinetic analyses show Aβ has a lower binding affinity in complexes with B56 subunits and exhibits unique aggregative properties as a monomeric protein. These findings suggest that the different physicochemical properties between A-subunit isoforms are key to PP2A holoenzyme assembly and function. We predict that the Aβ serves as a reservoir, ensuring that serine-threonine phosphatase activity is maintained during high regulatory demand.

Keywords: A-subunit; Aα; Aβ; PP2A; PPP2R1A; PPP2R1B; cryo-EM; isoform; phosphatase; scaffold.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests D.J.T. and G.N. have equity interests in RAPPTA therapeutics. The remaining authors declare no competing interests.

Similar articles

See all similar articles

References

    1. Brautigan DL, and Shenolikar S (2018). Protein Serine/Threonine Phosphatases: Keys to Unlocking Regulators and Substrates. Annual Review of Biochemistry 87, 921–964. 10.1146/annurev-biochem-062917-012332. - DOI - PubMed
    1. Junttila MR, Puustinen P, Niemelä M, Ahola R, Arnold H, Böttzauw T, Ala-aho R, Nielsen C, Ivaska J, Taya Y, et al. (2007). CIP2A Inhibits PP2A in Human Malignancies. Cell 130, 51–62. 10.1016/j.cell.2007.04.044. - DOI - PubMed
    1. Chen W, Possemato R, Campbell KT, Plattner CA, Pallas DC, and Hahn WC (2004). Identification of specific PP2A complexes involved in human cell transformation. Cancer Cell 5, 127–136. 10.1016/S1535-6108(04)00026-1. - DOI - PubMed
    1. Kurimchak A, and Graña X (2015). PP2A: more than a reset switch to activate pRB proteins during the cell cycle and in response to signaling cues. Cell Cycle 14, 18–30. 10.4161/15384101.2014.985069. - DOI - PMC - PubMed
    1. Eichhorn PJA, Creyghton MP, and Bernards R (2009). Protein phosphatase 2A regulatory subunits and cancer. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1795, 1–15. 10.1016/J.BBCAN.2008.05.005. - DOI - PubMed

LinkOut - more resources