Cited by 207Protein Tyrosine PhosphatasesProtein Kinase Regulation and GTPase SignalingEnzyme Structure and Function

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Structural Mechanism of Demethylation and Inactivation of Protein Phosphatase 2A

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Xing, Yongna, Li, Zhu, Chen, Yu, Stock, Jeffry B., Jeffrey, Philip D., Shi, Yigong·2008·Cell

DOI 10.1016/j.cell.2008.02.041

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Abstract

Protein phosphatase 2A (PP2A) is an important serine/threonine phosphatase that plays a role in many biological processes. Reversible carboxyl methylation of the PP2A catalytic subunit is an essential regulatory mechanism for its function. Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans. However, the underlying mechanism of PME-1 function remains enigmatic. Here we report the crystal structures of PME-1 by itself and in complex with a PP2A heterodimeric core enzyme. The structures reveal that PME-1 directly binds to the active site of PP2A and that this interaction results in the activation of PME-1 by rearranging the catalytic triad into an active conformation. Strikingly, these interactions also lead to inactivation of PP2A by evicting the manganese ions that are required for the phosphatase activity of PP2A. These observations identify a dual role of PME-1 that regulates PP2A activation, methylation, and holoenzyme assembly in cells.

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Authors: Xing, Y., Li, Z., Chen, Y., Stock, J. B., Jeffrey, P. D., & Shi, Y.
Affiliations: Princeton University (US)
Corresponding author: Shi, Yigong
ORCID: Xing, Yongna
Li, Zhu
Chen, Yu
Stock, Jeffry B.
Jeffrey, Philip D.
Shi, Yigong
Venue: Cell
Publisher: Elsevier BV
Published: 2008-04
Volume: 133
Issue: 1
Pages: 154-163
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2008.02.041
OpenAlex: W2012819402
Cited by: 206
References: 52
Citations by year: 2026: 8 · 2025: 10 · 2024: 9 · 2023: 9 · 2022: 11 · 2021: 14 · 2020: 8 · 2019: 12 · 2018: 15 · 2017: 4 · 2016: 17 · 2015: 9 · 2014: 12 · 2013: 9 · 2012: 19
FWCI: 5.34
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 1933 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Cancer Institute (K01CA124856, R01CA123155)
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 › Structural Biology › Enzyme Structure and Function
Keywords: protein phosphatase 2A, PME-1, carboxyl methylation, demethylation, PP2A catalytic subunit, catalytic triad, enzyme activation, enzyme inactivation, holoenzyme assembly, crystal structure
MeSH terms: Amino Acid Sequence, Animals, Carboxylic Ester Hydrolases, Humans, Methylation, Models, Molecular, Molecular Sequence Data, Sequence Alignment, Crystallography, X-Ray, Protein Phosphatase 2

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Structural Mechanism of Demethylation and Inactivation of Protein Phosphatase 2A

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