Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins
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The serine/threonine phosphatase protein phosphatase 2A (PP2A) plays an essential role in many aspects of cellular functions and has been shown to be an important tumor suppressor. The core enzyme of PP2A comprises a 65 kDa scaffolding subunit and a 36 kDa catalytic subunit. Here we report the crystal structures of the PP2A core enzyme bound to two of its inhibitors, the tumor-inducing agents okadaic acid and microcystin-LR, at 2.6 and 2.8 A resolution, respectively. The catalytic subunit recognizes one end of the elongated scaffolding subunit by interacting with the conserved ridges of HEAT repeats 11-15. Formation of the core enzyme forces the scaffolding subunit to undergo pronounced structural rearrangement. The scaffolding subunit exhibits considerable conformational flexibility, which is proposed to play an essential role in PP2A function. These structures, together with biochemical analyses, reveal significant insights into PP2A function and serve as a framework for deciphering the diverse roles of PP2A in cellular physiology.
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In complex with the core dimer, B-family subunits contact scaffold HEAT repeats 1-7 and make few contacts with the catalytic subunit.
“In complex with the core dimer, B-family subunits make several contacts with HEAT repeats 1–7 in the N-terminus of the scaffold but very few contacts with the catalytic subunit (Xing et al., 2006).”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Xing et al., 2006
The PP2A C subunit binds to the conserved ridge of HR 11-15, while the B′ regulatory subunit interacts with the ridge of HR 2-8.
“The C subunit binds to the conserved ridge of HR 11–15 [ 31 ], while the B′ regulatory subunit interacts with the ridge of HR 2–8 (Fig. 2 ) [ 27 ].”
From Targeting PP2A in cancer: an underrated option (2025) · cites this paper as [31]
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References 61 · Cited by 334
- Authors
- Xing, Y., Xu, Y., Chen, Y., Jeffrey, P. D., Chao, Y., Lin, Z., Li, Z., Strack, S., Stock, J. B., & Shi, Y.
- Affiliations
- Princeton University (US)
- University of Iowa (US)
- Corresponding author
- Shi, Yigong
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2006-10
- Volume
- 127
- Issue
- 2
- Pages
- 341-353
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2159527263
- Cited by
- 334
- References
- 61
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 15 · 2023: 13 · 2022: 13 · 2021: 16 · 2020: 19 · 2019: 21 · 2018: 15 · 2017: 12 · 2016: 22 · 2015: 12 · 2014: 15 · 2013: 27 · 2012: 15
- FWCI
- 7.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- 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
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- protein phosphatase 2A, okadaic acid, microcystin-LR, phosphatase inhibitors, catalytic subunit, HEAT repeats, protein-protein interaction, conformational flexibility, tumor suppressor, crystal structure
- MeSH terms
- Amino Acid Sequence, Bacterial Toxins, Binding Sites, Carcinogens, Crystallography, Humans, Marine Toxins, Methylation, Models, Molecular, Molecular Sequence Data, Phosphoprotein Phosphatases, Protein Binding, Protein Conformation, Okadaic Acid, Holoenzymes, Catalytic Domain, Microcystins, Protein Phosphatase 2
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