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

Journal Article · Sat Dec 31 04:00:00 EST 2011 · Molecular Cell

DOI:https://doi.org/10.1016/j.molcel.2010.12.030· OSTI ID:1042041

Stanevich, V; Jiang, L; Satyshur, K; Li, Y; Jeffrey, P; Li, Z; Menden, P; Semmelhack, M; Xing, Y

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: BROOKHAVEN NATIONAL LABORATORY (BNL)
• Sponsoring Organization: USDOE SC OFFICE OF SCIENCE (SC)
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 1042041
• Report Number(s): BNL--97719-2012-JA
• Journal Information: Molecular Cell, Journal Name: Molecular Cell Journal Issue: 3 Vol. 41; ISSN 1097-2765
• 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