The structural basis for tight control of PP2A methylation and function by LCMT-1
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Proper formation of protein phosphatase 2A (PP2A) holoenzymes is essential for the fitness of all eukaryotic cells. Carboxyl methylation of the PP2A catalytic subunit plays a critical role in regulating holoenzyme assembly; methylation is catalyzed by PP2A-specific methyltransferase LCMT-1, an enzyme required for cell survival. We determined crystal structures of human LCMT-1 in isolation and in complex with PP2A stabilized by a cofactor mimic. The structures show that the LCMT-1 active-site pocket recognizes the carboxyl terminus of PP2A, and, interestingly, the PP2A active site makes extensive contacts to LCMT-1. We demonstrated that activation of the PP2A active site stimulates methylation, suggesting a mechanism for efficient conversion of activated PP2A into substrate-specific holoenzymes, thus minimizing unregulated phosphatase activity or formation of inactive holoenzymes. A dominant-negative LCMT-1 mutant attenuates the cell cycle without causing cell death, likely by inhibiting uncontrolled phosphatase activity. Our studies suggested mechanisms of LCMT-1 in tight control of PP2A function, important for the cell cycle and cell survival.
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Carboxymethylation at L309 is reversibly controlled by LCMT-1 and PME-1.
“Carboxymethylation on L309 is reversibly controlled by two PP2A-specific enzymes, leucine carboxy methyltransferase (LCMT-1) and PP2A-specific methylesterase 1 (PME-1) (Stanevich et al., 2011; Xing et al., 2008).”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Stanevich et al., 2011
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- Authors
- Stanevich, V., Jiang, L., Satyshur, K. A., Li, Y., Jeffrey, P. D., Li, Z., Menden, P., Semmelhack, M. F., & Xing, Y.
- Affiliations
- University of Wisconsin–Madison (US)
- Princeton University (US)
- Signum Biosciences (United States) (US)
- Corresponding author
- Xing, Yongna
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2011-02
- Volume
- 41
- Issue
- 3
- Pages
- 331-342
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3060061
- OpenAlex
- W2135344630
- Cited by
- 142
- References
- 45
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 9 · 2023: 17 · 2022: 6 · 2021: 10 · 2020: 8 · 2019: 6 · 2018: 10 · 2017: 6 · 2016: 10 · 2015: 4 · 2014: 10 · 2013: 8 · 2012: 11
- FWCI
- 4.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (K01CA124856)
- 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 › Cancer-related gene regulation
- Keywords
- protein phosphatase 2A, PP2A catalytic subunit, carboxyl methylation, methyltransferase, holoenzyme assembly, protein-protein interaction, crystal structure, cell cycle regulation, cell survival, dominant-negative mutant
- MeSH terms
- Animals, Humans, Methylation, Models, Molecular, Mutation, Protein Binding, Protein O-Methyltransferase, Crystallography, X-Ray, Protein Structure, Quaternary, Cell Line, Tumor, Rats, Protein Phosphatase 2, Biocatalysis
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