Structural basis of PP2A activation by PTPA, an ATP-dependent activation chaperone
Open accessAbstract
Proper activation of protein phosphatase 2A (PP2A) catalytic subunit is central for the complex PP2A regulation and is crucial for broad aspects of cellular function. The crystal structure of PP2A bound to PP2A phosphatase activator (PTPA) and ATPγS reveals that PTPA makes broad contacts with the structural elements surrounding the PP2A active site and the adenine moiety of ATP. PTPA-binding stabilizes the protein fold of apo-PP2A required for activation, and orients ATP phosphoryl groups to bind directly to the PP2A active site. This allows ATP to modulate the metal-binding preferences of the PP2A active site and utilize the PP2A active site for ATP hydrolysis. In vitro, ATP selectively and drastically enhances binding of endogenous catalytic metal ions, which requires ATP hydrolysis and is crucial for acquisition of pSer/Thr-specific phosphatase activity. Furthermore, both PP2A- and ATP-binding are required for PTPA function in cell proliferation and survival. Our results suggest novel mechanisms of PTPA in PP2A activation with structural economy and a unique ATP-binding pocket that could potentially serve as a specific therapeutic target.
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The PP2A/C active site contains a Zn2+ ion, and ATP is needed to load a catalytic Mg2+ ion for activation.
“Guo et al. provide evidence that the active site is occupied by a Zn2+ ion and ATP is necessary for the loading of a catalytic Mg2+ ion for PP2A/C activation.”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Guo et al., 2014
PTPA stabilizes an active conformation of the catalytic site and mediates loading of catalytic metal ions.
“This is facilitated by the phosphotyrosyl phosphatase activator (PTPA), which is a specific for PP2A. PTPA plays a critical role in stabilizing an active conformation of the catalytic active site and mediates the loading of catalytic metal ions (Guo et al., 2014).”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Guo et al., 2014
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- Authors
- Guo, F., Stanevich, V., Wlodarchak, N., Sengupta, R., Jiang, L., Satyshur, K. A., & Xing, Y.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Xing, Yongna
- Venue
- Cell Research
- Published
- 2013-10-08
- Volume
- 24
- Issue
- 2
- Pages
- 190-203
- ISSN
- 1001-0602 (ISSN-L)
- 1748-7838
- PMC
- PMC3915903
- OpenAlex
- W2141968036
- Cited by
- 100
- References
- 47
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 7 · 2023: 6 · 2022: 15 · 2021: 12 · 2020: 7 · 2019: 8 · 2018: 5 · 2017: 13 · 2016: 5 · 2015: 2 · 2014: 6
- FWCI
- 1.94
- 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
- Universität Wien
- Medizinische Universität Wien
- National Cancer Institute (T32CA009135)
- National Institute of General Medical Sciences (R01GM096060)
- 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, PP2A activation, PTPA, ATP gamma S, crystal structure, metal ion binding, ATP hydrolysis, ATP binding site, cell proliferation, cell survival, therapeutic target
- MeSH terms
- Adenosine Triphosphate, Binding Sites, Enzyme Activation, HeLa Cells, Humans, Kinetics, Manganese, Phosphoprotein Phosphatases, Phosphorylation, Protein Binding, Mutagenesis, Site-Directed, Crystallography, X-Ray, Catalytic Domain, RNA Interference, RNA, Small Interfering, Protein Phosphatase 2
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