Effects of carboxyl-terminal methylation on holoenzyme function of the PP2A subfamily

Biochem Soc Trans. 2020 Oct 30;48(5):2015-2027. doi: 10.1042/BST20200177.


Phosphoprotein Phosphatases (PPPs) are enzymes highly conserved from yeast and human and catalyze the majority of the serine and threonine dephosphorylation in cells. To achieve substrate specificity and selectivity, PPPs form multimeric holoenzymes consisting of catalytic, structural/scaffolding, and regulatory subunits. For the Protein Phosphatase 2A (PP2A)-subfamily of PPPs, holoenzyme assembly is at least in part regulated by an unusual carboxyl-terminal methyl-esterification, commonly referred to as 'methylation'. Carboxyl-terminal methylation is catalyzed by Leucine carboxyl methyltransferase-1 (LCMT1) that utilizes S-adenosyl-methionine (SAM) as the methyl donor and removed by protein phosphatase methylesterase 1 (PME1). For PP2A, methylation dictates regulatory subunit selection and thereby downstream phosphorylation signaling. Intriguingly, there are four families of PP2A regulatory subunits, each exhibiting different levels of methylation sensitivity. Thus, changes in PP2A methylation stoichiometry alters the complement of PP2A holoenzymes in cells and creates distinct modes of kinase opposition. Importantly, selective inactivation of PP2A signaling through the deregulation of methylation is observed in several diseases, most prominently Alzheimer's disease (AD). In this review, we focus on how carboxyl-terminal methylation of the PP2A subfamily (PP2A, PP4, and PP6) regulates holoenzyme function and thereby phosphorylation signaling, with an emphasis on AD.

Keywords: phosphoprotein phosphatase; phosphorylation; signalling.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Alzheimer Disease / metabolism
  • Animals
  • Catalysis
  • Catalytic Domain
  • Dimerization
  • Enzymes / chemistry*
  • Gene Expression Regulation*
  • Holoenzymes / chemistry
  • Humans
  • Methylation
  • Mice
  • Mutation
  • Phosphoproteins / chemistry*
  • Phosphorylation
  • Protein Conformation
  • Protein Domains
  • Protein Phosphatase 2 / chemistry*
  • Protein Processing, Post-Translational
  • Protein Subunits / metabolism
  • Saccharomyces cerevisiae / metabolism
  • Signal Transduction
  • Substrate Specificity


  • Enzymes
  • Holoenzymes
  • Phosphoproteins
  • Protein Subunits
  • Protein Phosphatase 2