TY - JOUR
T1 - The Structural Basis for Tight Control of PP2A Methylation and Function by LCMT-1
AU - Stanevich, Vitali
AU - Jiang, Li
AU - Satyshur, Kenneth A.
AU - Li, Yongfeng
AU - Jeffrey, Philip D.
AU - Li, Zhu
AU - Menden, Patrick
AU - Semmelhack, Martin F.
AU - Xing, Yongna
N1 - Funding Information:
We thank Anand Saxena (National Synchrotron Light Source) and David Smith (Advanced Photon Source Life Sciences Collaborative Access Team) for assistance, Yigong Shi (Tsinghua University), David Pallas (Emory University), and David Brautigan (University of Virginia) for discussion, Andreas Friedl (University of Wisconsin at Madison) for the rat C6 glioma cell line, and Bill Sugden (University of Wisconsin at Madison) for discussion and the retrovirus vector. This work was supported by University of Wisconsin at Madison (Y.X.), National Institutes of Health fellowship K01 CA124856 (Y.X.), and American Cancer Society Research Scholar Grant RSG-10-153-01-DMC (Y.X).
PY - 2011/2/4
Y1 - 2011/2/4
N2 - 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.
AB - 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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U2 - 10.1016/j.molcel.2010.12.030
DO - 10.1016/j.molcel.2010.12.030
M3 - Article
C2 - 21292165
AN - SCOPUS:79251553753
SN - 1097-2765
VL - 41
SP - 331
EP - 342
JO - Molecular Cell
JF - Molecular Cell
IS - 3
ER -