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

Journal Article · Tue May 29 04:00:00 EDT 2012 · Mol. Cell

DOI:https://doi.org/10.1016/j.molcel.2010.12.030· OSTI ID:1033006

Stanevich, Vitali; Jiang, Li; Satyshur, Kenneth A; Li, Yongfeng; Jeffrey, Philip D; Li, Zhu; Menden, Patrick; Semmelhack, Martin F; Xing, Yongna ^[1]

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1. UW

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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE Office of Science (SC)
• OSTI ID: 1033006
• Journal Information: Mol. Cell, Journal Name: Mol. Cell Journal Issue: (3) ; 02, 2011 Vol. 41
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
CELL CYCLE
CRYSTAL STRUCTURE
ENZYMES
METHYLATION
MUTANTS
PHOSPHATASES
PROTEINS