The Structural Basis for Tight Control of PP2A Methylation and Function by LCMT-1

Vitali Stanevich, Li Jiang, Kenneth A. Satyshur, Yongfeng Li, Philip D. Jeffrey, Zhu Li, Patrick Menden, Martin F. Semmelhack, Yongna Xing

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)331-342
Number of pages12
JournalMolecular Cell
Volume41
Issue number3
DOIs
StatePublished - Feb 4 2011

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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    Stanevich, V., Jiang, L., Satyshur, K. A., Li, Y., Jeffrey, P. D., Li, Z., Menden, P., Semmelhack, M. F., & Xing, Y. (2011). The Structural Basis for Tight Control of PP2A Methylation and Function by LCMT-1. Molecular Cell, 41(3), 331-342. https://doi.org/10.1016/j.molcel.2010.12.030