Protein carboxyl methylation and the biochemistry of memory

Abstract Bacterial chemotaxis is mediated by two reversible protein modification chemistries: phosphorylation and carboxyl methylation. Attractants bind to membrane chemoreceptors that control the activity of a protein kinase which acts in turn to control flagellar motor activity. Coordinate changes in receptor carboxyl methylation provide a negative feedback mechanism that serves a memory function. Protein carboxyl methylation might play an analogous role in the nervous system. Two protein carboxyl methyltransferases serve to regulate signal transduction pathways in eukaryotic cells. One is highly expressed in the Purkinje layer of the cerebellum where it methyl esterifies prenylated cysteine residues at the carboxyl-termini of Ras-related and heterotrimeric G-proteins. The other is abundant throughout the brain where it methylates the carboxyl-terminus of protein phosphatase 2A. The phosphatase methyltransferase and the protein methylesterase that reverses phosphatase methylation are structurally related to the corresponding bacterial chemotaxis methylating and demethylating enzymes. Recent results indicate that deficiencies in phosphatase methylation play an important role in the etiology of Alzheimer's disease.

[1]  D. Koshland,et al.  Methyl-esterified proteins in a mammalian cell line. , 1985, Biochemistry.

[2]  I. Vetter,et al.  The Guanine Nucleotide-Binding Switch in Three Dimensions , 2001, Science.

[3]  P. Mehta.  Amyloid beta protein as a marker or risk factor of Alzheimer's disease. , 2007, Current Alzheimer research.

[4]  Etienne Waelkens,et al.  The Protein Phosphatase 2A Phosphatase Activator Is a Novel Peptidyl-Prolyl cis/trans-Isomerase* , 2006, Journal of Biological Chemistry.

[5]  M. Goedert,et al.  Protein Phosphatase 2A Is the Major Enzyme in Brain that Dephosphorylates τ Protein Phosphorylated by Proline‐Directed Protein Kinases or Cyclic AMP‐Dependent Protein Kinase , 1995 .

[6]  Ann M Stock,et al.  Two-component signal transduction. , 2000, Annual review of biochemistry.

[7]  J. Wegiel,et al.  Decrease of protein phosphatase 2A and its association with accumulation and hyperphosphorylation of tau in Down syndrome. , 2008, Journal of Alzheimer's disease : JAD.

[8]  Scott A. Small,et al.  Linking Aβ and Tau in Late-Onset Alzheimer's Disease: A Dual Pathway Hypothesis , 2008, Neuron.

[9]  E. Cox,et al.  Isoprenylcysteine carboxy methylation is essential for development in Dictyostelium discoideum. , 2007, Molecular biology of the cell.

[10]  Sung-Hou Kim,et al.  Four-helical-bundle structure of the cytoplasmic domain of a serine chemotaxis receptor , 1999, Nature.

[11]  C. White,et al.  Downregulation of Protein Phosphatase 2A Carboxyl Methylation and Methyltransferase May Contribute to Alzheimer Disease Pathogenesis , 2004, Journal of neuropathology and experimental neurology.

[12]  J. Adler,et al.  Protein methylation in behavioural control mechanisms and in signal transduction , 1979, Nature.

[13]  K. Iqbal,et al.  Alzheimer neurofibrillary degeneration , 2007, Journal of Molecular Neuroscience.

[14]  V. Janssens,et al.  PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail). , 2008, Trends in biochemical sciences.

[15]  Karen Zwaenepoel,et al.  Spatial control of protein phosphatase 2A (de)methylation. , 2008, Experimental cell research.

[16]  Khadija Iqbal,et al.  Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Sam A. Johnson,et al.  Kinomics: methods for deciphering the kinome , 2004, Nature Methods.

[18]  P. Cohen.  Classification of protein-serine/threonine phosphatases: identification and quantitation in cell extracts. , 1991, Methods in enzymology.

[19]  J. Stock,et al.  Methylation, demethylation, and deamidation at glutamate residues in membrane chemoreceptor proteins. , 1988, Advances in experimental medicine and biology.

[20]  S. Michaelis,et al.  Topological and mutational analysis of Saccharomyces cerevisiae Ste14p, founding member of the isoprenylcysteine carboxyl methyltransferase family. , 2001, Molecular biology of the cell.

[21]  John M. Walker,et al.  Potassium Channels , 2009, Methods in Molecular Biology.

[22]  R. Baron,et al.  Thematic review series: Lipid Posttranslational Modifications. Geranylgeranylation of Rab GTPases Published, JLR Papers in Press, January 9, 2006. , 2006, Journal of Lipid Research.

[23]  H. Berg,et al.  Chemotaxis in Escherichia coli analysed by Three-dimensional Tracking , 1972, Nature.

[24]  V. Sourjik,et al.  Spatial organization of the bacterial chemotaxis system. , 2006, Current opinion in microbiology.

[25]  Ann M Stock,et al.  Structural analysis of bacterial chemotaxis proteins: components of a dynamic signaling system. , 1998, Journal of structural biology.

[26]  P. Cohen,et al.  Protein phosphatase 2A is the major enzyme in brain that dephosphorylates tau protein phosphorylated by proline-directed protein kinases or cyclic AMP-dependent protein kinase. , 1995, Journal of neurochemistry.

[27]  Joanne I. Yeh,et al.  The three-dimensional structure of the ligand-binding domain of a wild-type bacterial chemotaxis receptor. Structural comparison to the cross-linked mutant forms and conformational changes upon ligand binding. , 1994, The Journal of biological chemistry.

[28]  Allan R. Jones,et al.  Genome-wide atlas of gene expression in the adult mouse brain , 2007, Nature.

[29]  Sudha Seshadri,et al.  Plasma Homocysteine as a Risk Factor for Dementia and Alzheimer's Disease , 2002 .

[30]  D. Pallas,et al.  A Novel Assay for Protein Phosphatase 2A (PP2A) Complexes In Vivo Reveals Differential Effects of Covalent Modifications on Different Saccharomyces cerevisiae PP2A Heterotrimers , 2005, Eukaryotic Cell.

[31]  D. Pallas,et al.  Leucine Carboxyl Methyltransferase-1 Is Necessary for Normal Progression through Mitosis in Mammalian Cells* , 2007, Journal of Biological Chemistry.

[32]  J. Aletta,et al.  Protein methylation: a signal event in post-translational modification. , 1998, Trends in biochemical sciences.

[33]  B. Hemmings,et al.  Differential methylation and altered conformation of cytoplasmic and nuclear forms of protein phosphatase 2A during cell cycle progression , 1995, The Journal of cell biology.

[34]  Yigong Shi,et al.  Structure of the Protein Phosphatase 2A Holoenzyme , 2006, Cell.

[35]  Carlos S. Moreno,et al.  Carboxymethylation of the PP2A Catalytic Subunit inSaccharomyces cerevisiae Is Required for Efficient Interaction with the B-type Subunits Cdc55p and Rts1p* , 2001, The Journal of Biological Chemistry.

[36]  I. Grundke‐Iqbal,et al.  I PP2A 1 Affects Tau Phosphorylation via Association with the Catalytic Subunit of Protein Phosphatase 2A* , 2008, Journal of Biological Chemistry.

[37]  J. Adler.  How motile bacteria are attracted and repelled by chemicals: an approach to neurobiology. Lecture held on the occasion of the receipt of the Otto-Warburg-Medaille 1986. , 1987, Biological chemistry Hoppe-Seyler.

[38]  J. Otto,et al.  Isoprenylcysteine Carboxyl Methyltransferase Deficiency in Mice* , 2001, The Journal of Biological Chemistry.

[39]  P. Casey,et al.  Post-prenylation-processing enzymes as new targets in oncogenesis , 2005, Nature Reviews Cancer.

[40]  H. Savolainen,et al.  Methanol and formic acid toxicity: biochemical mechanisms. , 1991, Pharmacology & toxicology.

[41]  W. Gordon-Krajcer,et al.  Homocysteine-induced acute excitotoxicity in cerebellar granule cells in vitro is accompanied by PP2A-mediated dephosphorylation of tau , 2009, Neurochemistry International.

[42]  Wenqing Xu,et al.  Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme , 2007, Nature.

[43]  Conrad C. Huang,et al.  UCSF Chimera—A visualization system for exploratory research and analysis , 2004, J. Comput. Chem..

[44]  Yigong Shi,et al.  Structure and mechanism of the phosphotyrosyl phosphatase activator. , 2006, Molecular cell.

[45]  S. Ficarro,et al.  Targeted Disruption of the PME-1 Gene Causes Loss of Demethylated PP2A and Perinatal Lethality in Mice , 2008, PloS one.

[46]  J. Broach,et al.  Carboxyl methylation of the phosphoprotein phosphatase 2A catalytic subunit promotes its functional association with regulatory subunits in vivo , 2000, The EMBO journal.

[47]  X. L. Wang,et al.  Interrelations between plasma homocysteine and intracellular S-adenosylhomocysteine. , 2000, Biochemical and biophysical research communications.

[48]  Philip D. Jeffrey,et al.  Structural Mechanism of Demethylation and Inactivation of Protein Phosphatase 2A , 2008, Cell.

[49]  V. Janssens,et al.  Selection of Protein Phosphatase 2A Regulatory Subunits Is Mediated by the C Terminus of the Catalytic Subunit* , 2007, Journal of Biological Chemistry.

[50]  B. Wadzinski,et al.  Methylated C-terminal leucine residue of PP2A catalytic subunit is important for binding of regulatory Balpha subunit. , 1999, The Biochemical journal.

[51]  Liisa Holm,et al.  DaliLite workbench for protein structure comparison , 2000, Bioinform..

[52]  D. Pallas,et al.  Methylation of the protein phosphatase 2A catalytic subunit is essential for association of Balpha regulatory subunit but not SG2NA, striatin, or polyomavirus middle tumor antigen. , 2001, Molecular biology of the cell.

[53]  J. Stock,et al.  Analysis of two-component signal transduction systems involved in transcriptional regulation. , 1996, Methods in enzymology.

[54]  J. Stock,et al.  Carboxyl methylation regulates phosphoprotein phosphatase 2A by controlling the association of regulatory B subunits , 2000, The EMBO journal.

[55]  Michalis V. Karamouzis,et al.  Post-translational modifications and regulation of the RAS superfamily of GTPases as anticancer targets , 2007, Nature Reviews Drug Discovery.

[56]  William Arbuthnot Sir Lane,et al.  A Protein Phosphatase Methylesterase (PME-1) Is One of Several Novel Proteins Stably Associating with Two Inactive Mutants of Protein Phosphatase 2A* , 1999, The Journal of Biological Chemistry.

[57]  M. Spillantini,et al.  Frontotemporal Dementia with Tau Pathology , 2007, Neurodegenerative Diseases.

[58]  Ann M Stock,et al.  Crystal structure of the catalytic domain of the chemotaxis receptor methylesterase, CheB. , 1995, Journal of molecular biology.

[59]  Posttranslational modification of the Ha-ras oncogene protein: evidence for a third class of protein carboxyl methyltransferases. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[60]  T. Mizuno,et al.  Compilation of all genes encoding two-component phosphotransfer signal transducers in the genome of Escherichia coli. , 1997, DNA research : an international journal for rapid publication of reports on genes and genomes.

[61]  Yigong Shi,et al.  Structure of Protein Phosphatase 2A Core Enzyme Bound to Tumor-Inducing Toxins , 2006, Cell.

[62]  S. Speciale,et al.  Altered Expression Levels of the Protein Phosphatase 2A ABαC Enzyme Are Associated with Alzheimer Disease Pathology , 2004, Journal of neuropathology and experimental neurology.

[63]  G. Weissmann,et al.  Carboxyl methylation of Ras-related proteins during signal transduction in neutrophils , 1993, Science.

[64]  R. Macnab,et al.  The gradient-sensing mechanism in bacterial chemotaxis. , 1972, Proceedings of the National Academy of Sciences of the United States of America.

[65]  T. Bottiglieri,et al.  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 , 2008, The Journal of Neuroscience.

[66]  Fei Liu,et al.  Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation , 2005, The European journal of neuroscience.

[67]  G. Wadhams,et al.  Making sense of it all: bacterial chemotaxis , 2004, Nature Reviews Molecular Cell Biology.

[68]  Anita Preininger,et al.  Insights into G protein structure, function, and regulation. , 2003, Endocrine reviews.

[69]  Dao-Wen Wang,et al.  Homocysteine induces tau phosphorylation by inactivating protein phosphatase 2A in rat hippocampus , 2008, Neurobiology of Aging.

[70]  E. Ogris,et al.  Generation of Active Protein Phosphatase 2A Is Coupled to Holoenzyme Assembly , 2007, PLoS biology.

[71]  B. Hemmings,et al.  The catalytic subunit of protein phosphatase 2A is carboxyl-methylated in vivo. , 1994, The Journal of biological chemistry.

[72]  R. Diaz-Arrastia,et al.  Protein Phosphatase 2A Methyltransferase Links Homocysteine Metabolism with Tau and Amyloid Precursor Protein Regulation , 2007, The Journal of Neuroscience.

[73]  Edouard Pearlstein,et al.  Invertebrate preparations and their contribution to neurobiology in the second half of the 20th century , 2007, Brain Research Reviews.

[74]  Yigong Shi,et al.  Structure of a protein phosphatase 2A holoenzyme: insights into B55-mediated Tau dephosphorylation. , 2008, Molecular cell.

[75]  J. Stock,et al.  Protein phosphatase 2A methylation: a link between elevated plasma homocysteine and Alzheimer's Disease , 2002, FEBS letters.

[76]  C Van Hoof,et al.  Purification of porcine brain protein phosphatase 2A leucine carboxyl methyltransferase and cloning of the human homologue. , 1999, Biochemistry.

[77]  M. Mumby.  The 3D structure of protein phosphatase 2A: new insights into a ubiquitous regulator of cell signaling. , 2007, ACS chemical biology.

[78]  J. S. Parkinson,et al.  Bacterial chemoreceptors: high-performance signaling in networked arrays. , 2008, Trends in biochemical sciences.

[79]  J. Spudich,et al.  Sensory rhodopsin II: functional insights from structure. , 2002, Current opinion in structural biology.

[80]  D. Koshland.  Bacterial chemotaxis in relation to neurobiology. , 1980, Annual review of neuroscience.

[81]  I. Grundke‐Iqbal,et al.  Tau pathology in Alzheimer disease and other tauopathies. , 2005, Biochimica et biophysica acta.

[82]  I. Grundke‐Iqbal,et al.  Alzheimer neurofibrillary degeneration: significance, etiopathogenesis, therapeutics and prevention , 2007, Journal of cellular and molecular medicine.

[83]  P. Casey,et al.  Genetic and pharmacologic analyses of the role of Icmt in Ras membrane association and function. , 2006, Methods in enzymology.

[84]  G. Muszyńska,et al.  Protein phosphatase 2A: variety of forms and diversity of functions. , 2001, Acta biochimica Polonica.

[85]  V. Janssens,et al.  Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. , 2001, The Biochemical journal.

[86]  J. Janin,et al.  Structure of Protein Phosphatase Methyltransferase 1 (PPM1), a Leucine Carboxyl Methyltransferase Involved in the Regulation of Protein Phosphatase 2A Activity* , 2003, Journal of Biological Chemistry.

[87]  Dong Hou Kim,et al.  Methotrexate decreases PP2A methylation and increases tau phosphorylation in neuron. , 2007, Biochemical and biophysical research communications.

[88]  J. Stock,et al.  Protein phosphatase 2A catalytic subunit is methyl-esterified at its carboxyl terminus by a novel methyltransferase. , 1993, The Journal of biological chemistry.

[89]  Leonard Petrucelli,et al.  The role of tau in neurodegeneration , 2009, Molecular Neurodegeneration.

[90]  Y. Fukada,et al.  Effects of carboxyl methylation of photoreceptor G protein gamma-subunit in visual transduction. , 1994, The Journal of biological chemistry.

[91]  M. Philips,et al.  Thematic review series: Lipid Posttranslational Modifications CAAX modification and membrane targeting of Ras Published, JLR Papers in Press, March 16, 2006. , 2006, Journal of Lipid Research.

[92]  G. Bloom,et al.  Molecular Interactions among Protein Phosphatase 2A, Tau, and Microtubules , 1999, The Journal of Biological Chemistry.

[93]  Eric R Kandel,et al.  In search of general mechanisms for long-lasting plasticity: Aplysia and the hippocampus. , 2003, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[94]  S. Clarke,et al.  Protein phosphatase 2A is reversibly modified by methyl esterification at its C-terminal leucine residue in bovine brain. , 1994, The Journal of biological chemistry.

[95]  C. van Hoof,et al.  An inactive protein phosphatase 2A population is associated with methylesterase and can be re-activated by the phosphotyrosyl phosphatase activator. , 2004, The Biochemical journal.

[96]  J. Stock,et al.  Signal transduction in bacteria , 1990, Nature.

[97]  J. Stock,et al.  Bacterial chemotaxis and the molecular logic of intracellular signal transduction networks. , 1991, Annual review of biophysics and biophysical chemistry.

[98]  J. Stock,et al.  A specific protein carboxyl methylesterase that demethylates phosphoprotein phosphatase 2A in bovine brain. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[99]  G. Bloom,et al.  Regulation of the Phosphorylation State and Microtubule-Binding Activity of Tau by Protein Phosphatase 2A , 1996, Neuron.

[100]  J. Stock,et al.  Signal transduction in bacterial chemotaxis. , 2006, BioEssays : news and reviews in molecular, cellular and developmental biology.

[101]  Uri Alon,et al.  Response regulator output in bacterial chemotaxis , 1998, The EMBO journal.

[102]  D. Barford,et al.  Crystal structure of the PP2A phosphatase activator: implications for its PP2A-specific PPIase activity. , 2006, Molecular cell.

[103]  Igor B Zhulin,et al.  Comparative genomic and protein sequence analyses of a complex system controlling bacterial chemotaxis. , 2007, Methods in enzymology.