Historical Background
Leucine carboxyl methyltransferase-1 and leucine carboxyl methyltransferase-2 (LCMT-1 and LCMT-2) are part of the methyltransferase superfamily (Petrossian and Clarke 2011). These enzymes transfer a methyl group from S-adenosylmethionine (SAM) to methyl-accepting substrates to produce the corresponding methylated product plus S-adenosylhomocysteine (SAH). Over 200 methyltransferase enzymes have been identified in the human genome, and almost a third of these have been linked to one or more different diseases. LCMT-1 (a.k.a. PPMT) was discovered by Lee and Stock (Lee and Stock 1993) as a protein phosphatase 2A (PP2A)-specific carboxyl methyltransferase (Fig. 1a). Posttranslational carboxyl methylation of PP2A plays a central role in the regulatory biochemistry of...
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Adams J, Kelso R, Cooley L. The kelch repeat superfamily of proteins: propellers of cell function. Trends Cell Biol. 2000;10:17–24.
Bennecib M, Gong C-X, Grundke-Iqbal I, Iqbal K. Role of protein phosphatase-2A and-1 in the regulation of GSK-3, cdk5 and cdc2 and the phosphorylation of tau in rat forebrain. FEBS Lett. 2000;485:87–93.
De Baere I, Derua R, Janssens V, Van Hoof C, Waelkens E, Merlevede W, et al. Purification of porcine brain protein phosphatase 2A leucine carboxyl methyltransferase and cloning of the human homologue. Biochemistry. 1999;38:16539–47.
Hwang J, Lee JA, Pallas DC. Leucine carboxyl methyltransferase 1 (LCMT-1) methylates protein phosphatase 4 (PP4) and protein phosphatase 6 (PP6) and differentially regulates the stable formation of different PP4 holoenzymes. J Biol Chem. 2016;291:21008–19 : jbc. M116. 739920.
Kuszczyk M, Gordon-Krajcer W, Lazarewicz JW. Homocysteine-induced acute excitotoxicity in cerebellar granule cells in vitro is accompanied by PP2A-mediated dephosphorylation of tau. Neurochem Int. 2009;55:174–80.
Lee J, Stock J. Protein phosphatase 2A catalytic subunit is methyl-esterified at its carboxyl terminus by a novel methyltransferase. J Biol Chem. 1993;268:19192–5.
Lee JA, Pallas DC. Leucine carboxyl methyltransferase-1 is necessary for normal progression through mitosis in mammalian cells. J Biol Chem. 2007;282:30974–84.
Lee K-W, Chen W, Junn E, Im J-Y, Grosso H, Sonsalla PK, et al. Enhanced phosphatase activity attenuates α-synucleinopathy in a mouse model. J Neurosci. 2011;31:6963–71.
Martin L, Magnaudeix A, Esclaire F, Yardin C, Terro F. Inhibition of glycogen synthase kinase-3β downregulates total tau proteins in cultured neurons and its reversal by the blockade of protein phosphatase-2A. Brain Res. 2009;1252:66–75.
Ogris E, Du X, Nelson KC, Mak EK, Yu XX, Lane WS, et al. A protein phosphatase methylesterase (PME-1) is one of several novel proteins stably associating with two inactive mutants of protein phosphatase 2A. J Biol Chem. 1999;274:14382–91.
Petrossian TC, Clarke SG. Uncovering the human methyltransferasome. Mol Cell Proteomics. 2011;10:M110. 000976. doi:10.1074/mcp.M110.0000976.
Sontag E, Luangpirom A, Hladik C, Mudrak I, Ogris E, Speciale S, White CL 3rd. Altered expression levels of the protein phosphatase 2A ABalphaC enzyme are associated with Alzheimer disease pathology. J Neuropathol Exp Neurol. 2004;63:287–301.
Sontag JM, Sontag E. Protein phosphatase 2A dysfunction in Alzheimer’s disease. Front Mol Neurosci. 2014;7:16.
Sontag J-M, Nunbhakdi-Craig V, Montgomery L, Arning E, Bottiglieri T, Sontag E. Folate deficiency induces in vitro and mouse brain region-specific downregulation of leucine carboxyl methyltransferase-1 and protein phosphatase 2A Bα subunit expression that correlate with enhanced tau phosphorylation. J Neurosci. 2008;28:11477–87.
Stanevich V, Jiang L, Satyshur KA, Li Y, Jeffrey PD, Li Z, et al. The structural basis for tight control of PP2A methylation and function by LCMT-1. Mol Cell. 2011;41:331–42.
Strack S, Westphal RS, Colbran RJ, Ebner FF, Wadzinski BE. Protein serine/threonine phosphatase 1 and 2A associate with and dephosphorylate neurofilaments. Mol Brain Res. 1997;49:15–28.
Suzuki Y, Noma A, Suzuki T, Ishitani R, Nureki O. Structural basis of tRNA modification with CO2 fixation and methylation by wybutosine synthesizing enzyme TYW4. Nucleic Acids Res. 2009;37:2910–25.
Tolstykh T, Lee J, Vafai S, Stock JB. Carboxyl methylation regulates phosphoprotein phosphatase 2A by controlling the association of regulatory B subunits. EMBO J. 2000;19:5682–91.
Vafai SB, Stock JB. Protein phosphatase 2A methylation: a link between elevated plasma homocysteine and Alzheimer’s Disease. FEBS Lett. 2002;518:1–4.
Wu J, Tolstykh T, Lee J, Boyd K, Stock JB, Broach JR. Carboxyl methylation of the phosphoprotein phosphatase 2A catalytic subunit promotes its functional association with regulatory subunits in vivo. EMBO J. 2000;19:5672–81.
Xing Y, Li Z, Chen Y, Stock JB, Jeffrey PD, Shi Y. Structural mechanism of demethylation and inactivation of protein phosphatase 2A. Cell. 2008;133:154–63.
Yu XX, Du X, Moreno CS, Green RE, Ogris E, Feng Q, et al. Methylation of the protein phosphatase 2A catalytic subunit is essential for association of Bα regulatory subunit but not SG2NA, striatin, or polyomavirus middle tumor antigen. Mol Biol Cell. 2001;12:185–99.
Acknowledgments
We would like to thank Audrey Potts and David J. McFall for their help in putting together this manuscript. JBS has a significant financial interest in Signum Biosciences, a company devoted to the discovery of therapeutics that target the PP2A carboxyl methylation system.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG
About this entry
Cite this entry
Melideo, S.L., Ha, J.Y., Stock, J.B. (2018). Leucine Carboxyl Methyltransferase. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham. https://doi.org/10.1007/978-3-319-67199-4_101594
Download citation
DOI: https://doi.org/10.1007/978-3-319-67199-4_101594
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-67198-7
Online ISBN: 978-3-319-67199-4
eBook Packages: Biomedical and Life SciencesReference Module Biomedical and Life Sciences