title: The structural basis for tight control of PP2A methylation and function by LCMT-1.
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.
authors.affiliation: McArdle Laboratory, Department of Oncology, School of Medicine and Public Health, University of Wisconsin at Madison, Madison, WI 53706, USA.
authors.forename: Vitali
authors.initials: V
authors.lastname: Stanevich
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Satyshur
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Li
authors.forename: Philip D
authors.initials: PD
authors.lastname: Jeffrey
authors.forename: Zhu
authors.initials: Z
authors.lastname: Li
authors.forename: Patrick
authors.initials: P
authors.lastname: Menden
authors.forename: Martin F
authors.initials: MF
authors.lastname: Semmelhack
authors.forename: Yongna
authors.initials: Y
authors.lastname: Xing
mesh_terms: D000818:Animals; D055162:Biocatalysis; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D008745:Methylation; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D011497:Protein O-Methyltransferase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000737:chemistry* / Q000378:metabolism; D020836:Protein Structure, Quaternary; D051381:Rats
chemical_list: C524761:LCMT1 protein, human; D011497:Protein O-Methyltransferase; D054648:Protein Phosphatase 2