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.
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October 2020
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Cover Image
Centrosomes are microtubule-organizing centres required for the asymmetric division of neural stem cells, which support neurodevelopment, as discussed in a mini-review by Robinson and colleagues (pages 2101–2115) In the cover image, microtubules are shown in yellow and neural stem cells (aPKC) are magenta. Image provided by Dorothy Lerit.
Review Article|
October 14 2020
Effects of carboxyl-terminal methylation on holoenzyme function of the PP2A subfamily
Isha Nasa;
1Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth College, Hanover, NH, U.S.A.
2Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center at Dartmouth, Lebanon, NH, U.S.A.
Correspondence: Isha Nasa (Isha.Nasa@Dartmouth.edu) or Arminja N. Kettenbach (Arminja.N.Kettenbach@Dartmouth.edu)
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Arminja N. Kettenbach
1Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth College, Hanover, NH, U.S.A.
2Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center at Dartmouth, Lebanon, NH, U.S.A.
Correspondence: Isha Nasa (Isha.Nasa@Dartmouth.edu) or Arminja N. Kettenbach (Arminja.N.Kettenbach@Dartmouth.edu)
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
July 22 2020
Revision Received:
September 14 2020
Accepted:
September 16 2020
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2020
Biochem Soc Trans (2020) 48 (5): 2015–2027.
Article history
Received:
July 22 2020
Revision Received:
September 14 2020
Accepted:
September 16 2020
Citation
Isha Nasa, Arminja N. Kettenbach; Effects of carboxyl-terminal methylation on holoenzyme function of the PP2A subfamily. Biochem Soc Trans 30 October 2020; 48 (5): 2015–2027. doi: https://doi.org/10.1042/BST20200177
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