Structure of the Ca2+-dependent PP2A heterotrimer and insights into Cdc6 dephosphorylation
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The B″/PR72 family of protein phosphatase 2A (PP2A) is an important PP2A family involved in diverse cellular processes, and uniquely regulated by calcium binding to the regulatory subunit. The PR70 subunit in this family interacts with cell division control 6 (Cdc6), a cell cycle regulator important for control of DNA replication. Here, we report crystal structures of the isolated PR72 and the trimeric PR70 holoenzyme at a resolution of 2.1 and 2.4 Å, respectively, and in vitro characterization of Cdc6 dephosphorylation. The holoenzyme structure reveals that one of the PR70 calcium-binding motifs directly contacts the scaffold subunit, resulting in the most compact scaffold subunit conformation among all PP2A holoenzymes. PR70 also binds distinctively to the catalytic subunit near the active site, which is required for PR70 to enhance phosphatase activity toward Cdc6. Our studies provide a structural basis for unique regulation of B″/PR72 holoenzymes by calcium ions, and suggest the mechanisms for precise control of substrate specificity among PP2A holoenzymes.
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The catalytic subunit contacts the C-terminal HEAT repeats of the scaffold, and its contacts with regulatory subunits differ among B families.
“The catalytic subunit interacts with the C-terminal HEAT repeats of the scaffold subunit (Fig. 1B); this is different from its contacts with regulatory subunits, which are unique for each B-family (Cho and Xu, 2007; Wlodarchak et al., 2013; Xu et al., 2008; Xu et al., 2006).”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Wlodarchak et al., 2013
N-terminal HEAT repeats of PP2A/A contact regulatory subunits, while C-terminal HEAT repeats 11-15 contact the catalytic subunit.
“It has been shown that N-terminal HEAT repeats of PP2A/A make contact with the various regulatory subunits, while C-terminal HEAT repeats (11–15) mediate contacts with the catalytic subunit (Cho and Xu, 2007; Wlodarchak et al., 2013; Xu et al., 2008; Xu et al., 2006)(Fig. 1B).”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Wlodarchak et al., 2013
The C-terminus of B′′ subunits binds the catalytic subunit and is thought to serve as a substrate-binding site, with CDC6 binding there.
“The C-terminus of B” subunits mediates binding to the catalytic subunit and is also thought to act as a substrate binding site, as known interactors including CDC6 have been shown to bind here (Davis et al., 2008; Wlodarchak et al., 2013).”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Wlodarchak et al., 2013
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- Authors
- Wlodarchak, N., Guo, F., Satyshur, K. A., Jiang, L., Jeffrey, P. D., Sun, T., Stanevich, V., Mumby, M. C., & Xing, Y.
- Affiliations
- University of Wisconsin–Madison (US)
- Princeton University (US)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Xing, Yongna
- Venue
- Cell Research
- Published
- 2013-06-11
- Volume
- 23
- Issue
- 7
- Pages
- 931-946
- ISSN
- 1001-0602 (ISSN-L)
- 1748-7838
- PMC
- PMC3698643
- OpenAlex
- W2110138808
- Cited by
- 72
- References
- 44
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 2 · 2023: 5 · 2022: 8 · 2021: 10 · 2020: 7 · 2019: 3 · 2018: 3 · 2017: 5 · 2016: 7 · 2015: 4 · 2014: 11 · 2013: 2
- FWCI
- 3.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Research (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- University of Wisconsin-Madison (T32 CA009135, GM86560)
- Tsinghua University
- National Institutes of Health
- National Cancer Institute (T32CA009135)
- National Institute of General Medical Sciences (GM86560, R01GM096060, R01GM086560)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- protein phosphatase 2A, calcium binding, holoenzyme structure, substrate specificity, cell cycle regulation, DNA replication
- MeSH terms
- Animals, Calcium, Humans, Phosphorylation, Substrate Specificity, Crystallography, X-Ray, Cell Cycle Proteins, Holoenzymes, Protein Subunits, Protein Phosphatase 2
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