Structure of protein phosphatase methyltransferase 1 (PPM1), a leucine carboxyl methyltransferase involved in the regulation of protein phosphatase 2A activity

J Biol Chem. 2004 Feb 27;279(9):8351-8. doi: 10.1074/jbc.M311484200. Epub 2003 Dec 4.

Abstract

The important role of the serine/threonine protein phosphatase 2A (PP2A) in various cellular processes requires a precise and dynamic regulation of PP2A activity, localization, and substrate specificity. The regulation of the function of PP2A involves the reversible methylation of the COOH group of the C-terminal leucine of the catalytic subunit, which, in turn, controls the enzyme's heteromultimeric composition and confers different protein recognition and substrate specificity. We have determined the structure of PPM1, the yeast methyltransferase responsible for methylation of PP2A. The structure of PPM1 reveals a common S-adenosyl-l-methionine-dependent methyltransferase fold, with several insertions conferring the specific function and substrate recognition. The complexes with the S-adenosyl-l-methionine methyl donor and the S-adenosyl-l-homocysteine product and inhibitor unambiguously revealed the co-substrate binding site and provided a convincing hypothesis for the PP2A C-terminal peptide binding site. The structure of PPM1 in a second crystal form provides clues to the dynamic nature of the PPM1/PP2A interaction.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Catalysis
  • Conserved Sequence
  • Humans
  • Methylation
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Phosphoprotein Phosphatases / chemistry
  • Phosphoprotein Phosphatases / metabolism*
  • Protein Folding
  • Protein Methyltransferases / chemistry*
  • Protein Methyltransferases / metabolism*
  • Protein Phosphatase 2
  • S-Adenosylmethionine / metabolism
  • Saccharomyces cerevisiae Proteins / chemistry*
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Sequence Alignment
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • Saccharomyces cerevisiae Proteins
  • S-Adenosylmethionine
  • Ppm1 protein, S cerevisiae
  • Protein Methyltransferases
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2

Associated data

  • PDB/1RJD
  • PDB/1RJE
  • PDB/1RJF
  • PDB/1RJG