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Protein Hypercitrullination in CNS Demyelinating Disease Reversed by PAD Inhibition

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Protein Deimination in Human Health and Disease

Abstract

Protein deimination (the conversion of peptide-bound arginine residues to citrulline) is a posttranslational modification which has important consequences for both protein structure and function. In this reaction shown in Fig. 11.1, the quanidino group of arginine is deiminated to citrulline. Each arginine deiminated is accompanied by the loss of positive charge, since citrulline is neutral. Thus, the deimination of several arginines in a protein results in large changes in total charge, causing major changes in protein structure and function. This will be abundantly demonstrated in this article, highlighting myelin basic protein (MBP) and its effects on myelin structure and stability. These devastating effects on myelin suggest a basic mechanism preceding demyelination in multiple sclerosis (MS), the most common neurological disease of humans, affecting about two million people worldwide.

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References

  • Alvord EC (1970) Acute disseminated encephalomyelitis and allergic encephalopathies. In: Vinken PI, Bruyan GW (eds) Handbook of clinical neurology, 9th edn. Elsevier, New York, NY, pp 560–571

    Google Scholar 

  • Bahreini SA, Jabalameli MR, Saadatnia M, Zahednasab H (2010) The role of non-HLA single nucleotide polymorphisms in multiple sclerosis susceptibility. J Neuroimmunol 229(1–2):5–15

    Article  PubMed  CAS  Google Scholar 

  • Bates IR, Libich DS, Wood DD, Moscarello MA, Harauz G (2002) An Arg/Lys→Gln mutant of recombinant murine myelin basic protein as a mimic of the deiminated form implicated in multiple sclerosis. Protein Expr Purif 25(2):330–341

    Article  PubMed  CAS  Google Scholar 

  • Ben-Nun A, Wekerle H, Cohen IR (1981) The rapid isolation of clonable antigen-specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis. Eur J Immunol 11(3):195–199

    Article  PubMed  CAS  Google Scholar 

  • Beniac DR, Wood DD, Palaniyar N, Ottensmeyer FP, Moscarello MA, Harauz G (1999) Marburg’s variant of multiple sclerosis correlates with a less compact structure of myelin basic protein. Mol Cell Biol Res Commun 1(1):48–51

    Article  PubMed  CAS  Google Scholar 

  • Bhattacharya SK, Crabb JS, Bonilha VL, Gu X, Takahara H, Crabb JW (2006) Proteomics implicates peptidyl arginine deiminase 2 and optic nerve citrullination in glaucoma pathogenesis. Invest Ophthalmol Vis Sci 47(6):2508–2514

    Article  PubMed  Google Scholar 

  • Boggs JM, Moscarello MA, Papahadopoulus D (1982) Structural organization of myelin – role of lipid protein interactions determined in model systems. In: Jost PC, Hays Griffith D (eds).Wiley, USA

    Google Scholar 

  • Boggs JM, Wood DD, Moscarello MA (1981) Hydrophobic and electrostatic interactions of myelin basic proteins with lipid. Participation of N-terminal and C-terminal portions. Biochemistry 20(5):1065–1073

    Article  PubMed  CAS  Google Scholar 

  • Boggs JM, Rangaraj G, Hill CM, Bates IR, Heng YM, Harauz G (2005) Effect of arginine loss in myelin basic protein, as occurs in its deiminated charge isoform, on mediation of actin polymerization and actin binding to a lipid membrane in vitro. Biochemistry 44(9):3524–3534

    Article  PubMed  CAS  Google Scholar 

  • Boggs JM (2008) Myelin basic protein interaction with actin and tubulin in vitro: binding assembly and regulation in myelin basic protein. Nova Science, New York, pp 141–167

    Google Scholar 

  • Boggs JM, Gao W, Hirahara Y (2008) Signal-transduction pathways involved in interaction of galactosylceramide/sulfatide containing liposomes with cultured oligodendrocytes and requirment for myelin basic protein and glycosphingolipids. J Neurosci Res 86(7):1448–1458

    Article  PubMed  CAS  Google Scholar 

  • Berridge MJ (1984) Inositol trisphosphate and diacylglycerol as second messengers. Biochem J 220(2):345–360

    PubMed  CAS  Google Scholar 

  • Boulias C, Moscarello MA (1994) ADP-ribosylation of human myelin basic protein. J Neurochem 63(1):351–359

    Article  PubMed  CAS  Google Scholar 

  • Brady GW, Murthy NS, Fein DB, Wood DD, Moscarello MA (1981a) The effect of basic myelin protein on multilayer membrane formation. Biophys J 34(2):345–350

    Article  PubMed  CAS  Google Scholar 

  • Brady GW, Fein DB, Wood DD, Moscarello MA (1981b) The interaction of basic proteins from normal and multiple sclerosis myelin with phosphatidylglycerol vesicles. FEBS Lett 125(2):159–160

    Article  PubMed  CAS  Google Scholar 

  • Carrillo-Vico A, Leech MD, Anderton SM (2010) Contribution of myelin autoantigen citrullination to T cell autoaggression in the central nervous system. J Immunol 184:2839–2846

    Article  PubMed  CAS  Google Scholar 

  • Chan CK, Ramwani J, Moscarello MA (1988) Myelin basic protein binds GTP at a single site in the N-Terminus. Biochem Biosphys Res Commun 152:1468–1473

    Article  CAS  Google Scholar 

  • Cheung WY (1980) Calmodulin plays a pivotal role in cellular regulation. Science 207(4426):19–27

    Article  PubMed  CAS  Google Scholar 

  • Curis E, Nicolis I, Moinard C, Osowska S, Zerrouk N, Bénazeth S, Cynober L (2005) Almost all about citrulline in mammals. Amino Acids 29(3):177–205

    Article  PubMed  CAS  Google Scholar 

  • Cuthbert GL, Daujat S, Snowden AW, Erdjument-Bromage H, Hagiwara T, Yamada M, Schneider R, Gregory PD, Tempst P, Bannister AJ, Kouzarides T (2004) Histone deimination antagonizes arginine methylation. Cell 118(5):545–553

    Article  PubMed  CAS  Google Scholar 

  • Cuzner ML, Davison AN (1973) Changes in cerebral lysosomal enzyme activity and lipids in multiple sclerosis. J Neurol Sci 19(1):29–36

    Article  PubMed  CAS  Google Scholar 

  • Deber CM, Hughes DW, Fraser PE, Pawagi AB, Moscarello MA (1986) Binding of human normal and multiple sclerosis-derived myelin basic protein to phospholipid vesicles: effects on membrane head group and bilayer regions. Arch Biochem Biophys 245(2):455–463

    Article  PubMed  CAS  Google Scholar 

  • D’Souza CA, Wood DD, She YM, Moscarello MA (2005) Autocatalytic cleavage of myelin basic protein: an alternative to molecular mimicry. Biochemistry 44(38):12905–12913

    Article  PubMed  Google Scholar 

  • Dyer CA (1993) Novel oligodendrocyte transmembrane signalling system. Mol Neurobiol 7:1–22

    Article  PubMed  CAS  Google Scholar 

  • Ehrlich A, Booher S, Becerra Y, Borris DL, Figg WD, Turner ML, Blauvelt A (2004) Micellar paclitaxel improves severe psoriasis in a prospective phase II pilot study. J Am Acad Dermatol 50(4):533–540

    Article  PubMed  Google Scholar 

  • Epand RM, Moscarello MA, Zierenberg B, Vail WJ (1974a) The folded conformation of the encephalitogenic protein of the human brain. Biochemistry 13(6):1264–1267

    Article  PubMed  CAS  Google Scholar 

  • Epand RM, Wheeler GE, Moscarello MA (1974b) Circular dichroism and proton magnetic resonance studies of random chain poly-L-lysine. Biopolymers 13(2):359–369

    Article  PubMed  CAS  Google Scholar 

  • Eronina TB, Livanova NB, Chebotareva NA, Kurganov BI, Luo S, Graves DJ (1996) Deimination of glycogen phosphorylase b by peptidylarginine deiminase. Influence on the kinetic characteristics and dimer-tetramer transition. Biochimie 78(4):253–258

    Article  PubMed  CAS  Google Scholar 

  • Finch PR, Wood DD, Moscarello MA (1971) The presence of citrulline in a myelin protein fraction. FEBS Lett 15(2):145–148

    Article  PubMed  CAS  Google Scholar 

  • Genain CP, Nguyen MH, Letvin NL, Pearl R, Davis RL, Adelman M, Lees MB, Linington C, Hauser SL (1995) Antibody facilitation of multiple sclerosis-like lesions in a nonhuman primate. J Clin Invest 96(6):2966–2974

    Article  PubMed  CAS  Google Scholar 

  • Hagiwara T, Nakashima K, Hirano H, Senshu T, Yamada M (2002) Deimination of arginine residues in nucleophosmin/B23 and histones in HL-60 granulocytes. Biochem Biophys Res Commun 290(3):979–983

    Article  PubMed  CAS  Google Scholar 

  • Hill CM, Harauz G (2005) Charge effects modulate actin assembly by classic myelin basic protein isoforms. Biochem Biophys Res Commun 329(1):362–369

    Article  PubMed  CAS  Google Scholar 

  • Hashim GA, Wood DD, Moscarello MA (1980) Myelin lipophilin-induced demyelinating disease of the central nervous system. Neurochem Res 5(10):1137–1145

    Article  PubMed  CAS  Google Scholar 

  • Iglesias A, Bauer J, Litzenburger T, Schubart A, Linington C (2001) T- and B-cell responses to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis and multiple sclerosis. Glia 36(2):220–234

    Article  PubMed  CAS  Google Scholar 

  • International Multiple Sclerosis Consortium and Welcome Trust Control Consortium 2 (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476:214–219

    Article  Google Scholar 

  • Ishiyama N, Bates IR, Hill CM, Wood DD, Matharu P, Viner NJ, Moscarello MA, Harauz G (2001) The effects of deimination of myelin basic protein on structures formed by its interaction with phosphoinositide-containing lipid monolayers. J Struct Biol 136(1):30–45

    Article  PubMed  CAS  Google Scholar 

  • Ishigami A, Ohsawa T, Hiratsuka M, Taguchi H, Kobayashi S, Saito Y, Murayama S, Asaga H, Toda T, Kimura N, Maruyama N (2005) Abnormal accumulation of citrullinated proteins catalyzed by peptidylarginine deiminase in hippocampal extracts from patients with Alzheimer’s disease. J Neurosci Res 80(1):120–128

    Article  PubMed  CAS  Google Scholar 

  • Jang B, Jin JK, Jeon YC, Cho HJ, Ishigami A, Choi KC, Carp RI, Maruyama N, Kim YS, Choi EK (2010) Involvement of peptidylarginine deiminase-mediated post-translational citrullination in pathogenesis of sporadic Creutzfeldt–Jakob disease. Acta Neuropathol 119(2):199–210

    Article  PubMed  CAS  Google Scholar 

  • Jang B, Kim E, Choi JK, Jin JK, Ishigami A et al (2008) Accumulation of citrullinated proteins by up regulated peptidyarginine deiminase 2 in brains of scrapie infected mice: a possible role in pathogenesis. Am J Pathol 173:1129–1142

    Article  PubMed  CAS  Google Scholar 

  • Johnson RS, Roder JC, Riordan JR (1995) Over-expression of the DM-20 myelin proteolipid causes central nervous system demyelination in transgenic mice. J Neurochem 64:967–976

    Article  PubMed  CAS  Google Scholar 

  • Johnson EM, Maeno H, Greengard P (1971) Phosphorylation of endogenous protein of rat brain by cyclic adenosine 3′, 5′-monophosphate-dependent protein kinase. J Biol Chem 246(24):7731–7739

    PubMed  CAS  Google Scholar 

  • Kanter JL, Narayana S, Ho PP, Catz I, Warren KG, Sobel RA, Steinman L, Robinson WH (2006) Lipid microarrays identify key mediators of autoimmune brain inflammation. Nat Med 12(1):138–143

    Article  PubMed  CAS  Google Scholar 

  • Koga Y, Ohtake R (1914) Study report on the constituents of squeezed watermelon. J Tokyo Chem Soc 35:519–528

    Google Scholar 

  • Lamensa JW, Moscarello MA (1993) Deimination of human myelin basic protein by a peptidylarginine deiminase from bovine brain. J Neurochem 61(3):987–996

    Article  PubMed  CAS  Google Scholar 

  • Lange S, Gogel S, Leung KY, Vernay B, Ap V, Sausey CP, Thompson PR, Greene NDD, Feretti P (2011) Protein deiminases: new players in the developmentally regulated loss of regenerative ability. Dev Biol 355:204–214

    Article  Google Scholar 

  • Lebar R, Lubetzki C, Vincent C, Lombrail P, Boutry JM (1986) The M2 autoantigen of central nervous system myelin, a glycoprotein present in oligodendrocyte membrane. Clin Exp Immunol 66(2):423–434

    PubMed  CAS  Google Scholar 

  • Libich DS, Hill CM, Haines JD, Harauz G (2003a) Myelin basic protein has multiple calmodulin-binding sites. Biochem Biophys Res Commun 308(2):313–319

    Article  PubMed  CAS  Google Scholar 

  • Lopez-Diego RS, Weiner HL (2008) Novel therapeutic strategies for multiple sclerosis – a multi-faceted adversary. Nat Rev Drug Discov 7:909–925

    Article  PubMed  CAS  Google Scholar 

  • Libich DS, Hill CM, Bates IR, Hallett FR, Armstrong S, Siemiarczuk A, Harauz G (2003b) Interaction of the 18.5-kD isoform of myelin basic protein with Ca2+ -calmodulin: effects of deimination assessed by intrinsic Trp fluorescence spectroscopy, dynamic light scattering, and circular dichroism. Protein Sci 12(7):1507–1521

    Article  PubMed  CAS  Google Scholar 

  • Linington C, Bradl M, Lassmann H, Brunner C, Vass K (1988) Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin/oligodendrocyte glycoprotein. Am J Pathol 130(3):443–454

    PubMed  CAS  Google Scholar 

  • Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H (2000) Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Nuerol 47:707–717

    Article  CAS  Google Scholar 

  • Ludwin SK (2006) The pathogenesis of multiple sclerosis: relating human pathology to experimental studies. J Neuropathol Exp Neurol 65(4):305–318

    Article  PubMed  Google Scholar 

  • Li P, Li M, Lindberg MR, Kennett MJ, Na X, Wang Y (2010) PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med 207:1853–1862

    Article  PubMed  CAS  Google Scholar 

  • Liu GY, Liao YF, Chang WH, Liu CC, Hsieh MC, Hsu PC, Tsay GJ, Hung HC (2006) Overexpression of peptidylarginine deiminase IV features in apoptosis of haematopoietic cells. Apoptosis 11:183–196

    Article  PubMed  CAS  Google Scholar 

  • Mastronardi FG, Ackerley CA, Arsenault L, Roots BI, Moscarello MA (1993) Demyelination in a transgenic mouse: a model for multiple sclerosis. J Neurosci Res 36:315–324

    Article  PubMed  CAS  Google Scholar 

  • Mastronardi FG, Min W, Wang H, Winer S, Dosch M, Boggs JM, Moscarello MA (2004) Attenuation of experimental autoimmune encephalomyelitis and nonimmune demyelination by IFN-beta plus vitamin B12: treatment to modify notch-1/sonic hedgehog balance. J Immunol 172:6418–6426

    PubMed  CAS  Google Scholar 

  • Mastronardi FG, Wood DD, Mei J, Raijmakers R, Tseveleki V, Dosch HM, Probert L, Casaccia-Bonnefil P, Moscarello MA (2006) Increased citrullination of histone H3 in multiple sclerosis brain and animal models of demyelination: a role for tumor necrosis factor-induced peptidylarginine deiminase 4 translocation. J Neurosci 26(44):11387–11396

    Article  PubMed  CAS  Google Scholar 

  • Mastronardi FG, Noor A, Wood DD, Paton T, Moscarello MA (2007) Peptidylarginine deiminase 2 CpG island in multiple sclerosis white matter is hypomethylated. J Neurosci Res 85:2006–2016

    Article  PubMed  CAS  Google Scholar 

  • Miyamoto E (1975) Protein kinases in myelin of rat brain: solubilization and characterization. J Neurochem 24(3):503–512

    Article  PubMed  CAS  Google Scholar 

  • Miyamoto E, Miyazaki K, Hirose R, Kashiba A (1978) Multiple forms of protein kinases in myelin and microsomal fractions of bovine brain. J Neurochem 31(1):269–275

    Article  PubMed  CAS  Google Scholar 

  • Moscarello MA, Wood DD, Ackerley C, Boulias C (1994) Myelin in multiple sclerosis is developmentally immature. J Clin Invest 94(1):146–154

    Article  PubMed  CAS  Google Scholar 

  • Moscarello MA, Lei H, Mastronardi FG, Winer S, Tsui H, Li Z, Ackerley C, Li Z, Raijmakers R, Wood DD (2013) Inhibition of peptidylarginine deiminases reverses protein hypercitrullination and disease in mouse models of multiple sclerosis. Dis Model Mech 6:467–478

    Article  PubMed  CAS  Google Scholar 

  • Moscarello MA, Pritzker L, Mastronardi FG, Wood DD (2002) Peptidylarginine deiminase: a candidate factor in demyelinating disease. J Neurochem 81:335–343

    Article  PubMed  CAS  Google Scholar 

  • Murray N, Steck AJ (1986) Activation of myelin protein kinase by diacylglycerol and 4 beta-phorbol 12-myristate 13-acetate. J Neurochem 46(5):1655–1657

    Article  PubMed  CAS  Google Scholar 

  • Musse AA, Li Z, Ackerley CA, Bienzle D, Lei H, Poma R, Harauz G, Moscarello MA, Mastronardi FG (2008) Peptidylarginine deiminase 2 (PAD2) overexpression in transgenic mice leads to myelin loss in the central nervous system. Dis Model Mech 1:229–240

    Article  PubMed  CAS  Google Scholar 

  • Nakashima K, Hagiwara T, Yamada M (2002) Nuclear localization of peptidylarginine deiminase V and histone deimination in granulocytes. J Biol Chem 277(51):49562–49568

    Article  PubMed  CAS  Google Scholar 

  • Noseworthy JH (1999) Progress in determining the causes and treatment of multiple sclerosis. Nature 399:A40–A47

    Article  PubMed  CAS  Google Scholar 

  • Ochoa JL, Porath J, Kempf J, Egly JM (1980) Electron donor–acceptor properties of urea and its role in charge transfer chromatography. J Chromat 188:252–261

    Article  Google Scholar 

  • Odake KJ (1914) Tokyo Chem Soc 35:518

    Google Scholar 

  • Okensberg JR, Barnzini SE, Sawcer S, Hauser SL (2008) The genetics of multiple schlerosis: SNPs to pathogenesis. Nat Rev Genet 9:516–528

    Article  Google Scholar 

  • Peterson JW, Bo L, Mork S, Chang A, Trapp BD (2001) Transected neuritis, apoptotic neurons and reduced inflammation in cortical MS lesions. Ann Neurol 50:389–400

    Article  PubMed  CAS  Google Scholar 

  • Polverini E, Rangaraj G, Libich DS, Boggs JM, Harauz G (2008) Binding of the proline-rich segment of myelin basic protein to SH3 domains: spectroscopic, microarray, and modeling studies of ligand conformation and effects of posttranslational modifications. Biochemistry 47(1):267–282

    Article  PubMed  CAS  Google Scholar 

  • Polverini E, Boggs JM, Bates IR, Harauz G, Cavatorta P (2004) Electron paramagnetic resonance spectroscopy and molecular modelling of the interaction of myelin basic protein (MBP) with calmodulin (CaM)-diversity and conformational adaptability of MBP CaM-targets. J Struct Biol 148(3):353–369

    Article  PubMed  CAS  Google Scholar 

  • Pritzker LB, Joshi S, Gowan JJ, Harauz G, Moscarello MA (2000) Deimination of myelin basic protein. 1. Effect of deimination of arginyl residues of myelin basic protein on its structure and susceptibility to digestion by cathepsin D. Biochemistry 39(18):5374–5381

    Article  PubMed  CAS  Google Scholar 

  • Raijmakers R, Zendman AJ, Egberts WV, Vossenaar ER, Raats J, Soede-Huijbregts C, Rutjes FP, van Veelen PA, Drijfhout JW, Pruijn GJ (2007) Methylation of arginine residues interferes with citrullination by peptidylarginine deiminases in vitro. J Mol Biol 367(4):1118–1129

    Article  PubMed  CAS  Google Scholar 

  • Ramwani J, Moscarello MA (1990) Phosphorylation of charge isomers (components) of human myelin basic protein: identification of phosphorylated sites. J Neurochem 55(5):1703–1710

    Article  PubMed  CAS  Google Scholar 

  • Sprangers R, Groves MR, Sinning I, Sattler M (2003) High-resolution X-ray and NMR structures of the SMN Tudor domain: conformational variation in the binding site for symmetrically dimethylated arginine residues. J Mol Biol 327(2):507–520

    Article  PubMed  CAS  Google Scholar 

  • Sperber BR, Boyle-Walsh EA, Engleka MJ, Gadue P, Peterson AC, Stein PL, Scherer SS, McMorris FA (2001) A unique role for Fyn in CNS myelination. J Neurosci 21(6):2039–2047

    PubMed  CAS  Google Scholar 

  • Stys PK, Zamponi GW, van Minnen J, Guerts JJ (2012) Will the real multiple sclerosis please stand up? Nat Rev Neurosci 13:507–514

    Article  PubMed  CAS  Google Scholar 

  • Sulakhe PV, Petrali EH, Raney BI (1982) A highly active calcium ion stimulated endogenous protein kinase: kinetics and other characteristics, calmodulin dependence and comparison with other brain kinases. Plenum, New York, pp 281–301

    Google Scholar 

  • Schluesener HJ, Sobel RA, Linington C, Weiner HL (1987) A monoclonal antibody against a myelin oligodendrocyte glycoprotein induces relapses and demyelination in central nervous system autoimmune disease. J Immunol 139(12):4016–4021

    PubMed  CAS  Google Scholar 

  • Sospedra M, Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol 23:683–747

    Article  PubMed  CAS  Google Scholar 

  • Steinman L, Zamvil SS (2006) Multiple sclerosis in need of a critical reappraisal. Med Hypothesis 54:99–106

    Google Scholar 

  • Stone EM, Schaller TH, Bianchi H, Person MD, Fast W (2005) Inactivation of two diverse enzymes in the amidinotransferase superfamily by 2-chloroacetamidine: dimethylargininase and peptidylarginine deiminase. Biochemistry 44:13744–13752

    Article  PubMed  CAS  Google Scholar 

  • Tillak R, Breden P, Martin R, Sospendra M (2012) T-Lymphocyte priming of neutrophil extracellular traps links innate and adaptive immune responses. J Immunol 188:3150–3159

    Article  Google Scholar 

  • Tompkins TA, Moscarello MA (1991) A 57-kDa phosphatidylinositol-specific phospholipase C from bovine brain. J Biol Chem 266(7):4228–4236

    PubMed  CAS  Google Scholar 

  • Tompkins TA, Moscarello MA (1993) Stimulation of bovine brain phospholipase C activity by myelin basic protein requires arginyl residues in peptide linkage. Arch Biochem Biophys 302(2):476–483

    Article  PubMed  CAS  Google Scholar 

  • Trapp BD, Nave K-A (2008) Multiple sclerosis: an immune or neurodegenerative disorder? Neurosciences 31:247–269

    CAS  Google Scholar 

  • Tsai SC, Noda M, Adamik R, Chang PP, Chen HC, Moss J, Vaughan M (1988) Stimulation of choleragen enzymatic activities by GTP and two soluble proteins purified from bovine brain. J Biol Chem 263(4):1768–1772

    PubMed  CAS  Google Scholar 

  • Turner RS, Chou CH, Kibler RF, Kuo JF (1982) Basic protein in brain myelin is phosphorylated by endogenous phospholipid-sensitive Ca2+-dependent protein kinase. J Neurochem 39(5):1397–1404

    Article  PubMed  CAS  Google Scholar 

  • Tuohy VK, Thomas DM, Haqqi T, Yu M, Johnson JM (1995) Determinant-regulated onset of experimental autoimmune encephalomyelitis: distinct epitopes of myelin proteolipid protein mediate either acute or delayed disease in SJL/J mice. Autoimmunity 21:203–214

    Article  PubMed  CAS  Google Scholar 

  • Vandekerckhove J, Schering B, Bärmann M, Aktories K (1987) Clostridium perfringensiota toxin ADP-ribosylates skeletal muscle actin in Arg-177. FEBS Lett 225(1–2):48–52

    Article  PubMed  CAS  Google Scholar 

  • Van Dop C, Tsubokawa M, Bourne HR, Ramachandran J (1984) Amino acid sequence of retinal transducin at the site ADP-ribosylated by cholera toxin. J Biol Chem 259(2):696–698

    PubMed  Google Scholar 

  • Vossenaar ER, Zendman AJ, van Venrooij WJ, Pruijn GJ (2003) PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. Bioessays 25(11):1106–18, Review

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Wysocka J, Sayegh J, Lee YH, Perlin JR, Leonelli L, Sonbuchner LS, McDonald CH, Cook RG, Dou Y, Roeder RG, Clarke S, Stallcup MR, Allis CD, Coonrod SA (2004) Human PAD4 regulates histone arginine methylation levels via demethylimination. Science 306(5694):279–283

    Article  PubMed  CAS  Google Scholar 

  • Wood DD, Ackerley CA, Brand B, Zhang L, Raijmakers R, Mastronardi FG, Moscarello MA (2008) Myelin localization of peptidylarginine deiminases 2 and 4: comparison of PAD2 and PAD4 activities. Lab Invest 88(4):354–364

    Article  PubMed  CAS  Google Scholar 

  • Wood DD, Bilbao JM, O’Connors P, Moscarello MA (1996) Acute multiple sclerosis (Marburg type) is associated with developmentally immature myelin basic protein. Ann Neurol 40(1):18–24

    Article  PubMed  CAS  Google Scholar 

  • Wood DD, Moscarello MA (1997) Molecular biology of microglia: components of myelin–myelin bask protein – the implication of post-translational changes for demyelinating disease. Wiley, West Sussex, pp 37–54

    Google Scholar 

  • Wood DD, Moscarello MA (1989) The isolation, characterization, and lipid-aggregating properties of a citrulline containing myelin basic protein. J Biol Chem 264(9):5121–5127

    PubMed  CAS  Google Scholar 

  • Yon M, Ackerley CA, Mastronardi FG, Groome N, Moscarello MA (1996) Identification of a mitogen-activated protein kinase site in human myelin basic protein in situ. J Neuroimmunol 65(1):55–59

    Article  PubMed  CAS  Google Scholar 

  • Young DS, Meersman F, Oxley D, Webster J, Gill AC, Bronstein I, Lowe CR, Dear DV (2009) Effect of enzymatic deimination on the conformation of recombinant prion protein. Biochim Biophys Acta 1794(8):1123–33

    Article  PubMed  CAS  Google Scholar 

  • Zhu B, Guleria I, Khosroshahi A, Chitnis T, Imitola J, Azuma M, Yagita H, Sayegh MH, Khoury SJ (2006) Differential role of programmed death-ligand 1 [corrected] and programmed death-ligand 2 [corrected] in regulating the susceptibility and chronic progression of experimental autoimmune encephalomyelitis. J Immunol 176:3480–3489

    PubMed  CAS  Google Scholar 

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  1. The Hospital for Sick Children Research Institute, 555 University Ave., Toronto, ON, Canada, M5G 1X8

    Mario A. Moscarello

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  1. Department of Neurology, University of Alabama at Birmingham and The Birmingham Veterans Administration Medical Center, Birmingham, Alabama, USA

    Anthony P. Nicholas

  2. Bascom Palmer Eye Institute, University of Miami, MIAMI, Florida, USA

    Sanjoy K. Bhattacharya

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Moscarello, M.A. (2014). Protein Hypercitrullination in CNS Demyelinating Disease Reversed by PAD Inhibition. In: Nicholas, A., Bhattacharya, S. (eds) Protein Deimination in Human Health and Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8317-5_11

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