Neurochemical Research

, Volume 32, Issue 2, pp 137–158 | Cite as

A Tale of Two Citrullines—Structural and Functional Aspects of Myelin Basic Protein Deimination in Health and Disease

  • George Harauz
  • Abdiwahab A. Musse
Original Paper


Myelin basic protein (MBP) binds to negatively charged lipids on the cytosolic surface of oligodendrocyte membranes and is responsible for adhesion of these surfaces in the multilayered myelin sheath. The pattern of extensive post-translational modifications of MBP is dynamic during normal central nervous system (CNS) development and during myelin degeneration in multiple sclerosis (MS), affecting its interactions with the myelin membranes and with other molecules. In particular, the degree of deimination (or citrullination) of MBP is correlated with the severity of MS, and may represent a primary defect that precedes neurodegeneration due to autoimmune attack. That the degree of MBP deimination is also high in early CNS development indicates that this modification plays major physiological roles in myelin assembly. In this review, we describe the structural and functional consequences of MBP deimination in healthy and diseased myelin.


Citrulline Deimination Peptidylarginine deiminase Multiple sclerosis Myelin Myelin basic protein Rheumatoid arthritis 



Adenosine diphosphate


α-N-benzoyl-l-arginine ethyl ester


MBP charge components 1–8 (h—human, b—bovine, rm—recombinant murine)






Citrullinated (deiminated) MBP


Central nervous system




Experimental allergic/autoimmune encephalomyelitis


Electron paramagnetic resonance


Glial fibrillary acidic protein


Genes of the oligodendrocyte lineage


High-performance liquid chromatography


Microtubule-associated protein


Myristoylated alanine-rich C kinase substrate


Myelin basic protein (hMBP human, bMBP bovine, mMBP murine, rmMBP recombinant murine)


Myelin/oligodendrocyte glycoprotein


Multiple sclerosis


Nicotinamide adenine dinucleotide phosphate (oxidised/reduced)


Peptidylarginine deiminase, EC


Polyacrylamide gel electrophoresis




Phospholipase C



rmC1, rmC8

Recombinant murine analogues of natural C1, C8 isomers


Sodium dodecyl sulphate


Site-directed spin labelling



Our work has been supported by grants to GH from the Natural Sciences and Engineering Research Council of Canada, the Multiple Sclerosis Society of Canada (MSSC), and the Canadian Institutes for Health Research. AAM is the recipient of an MSSC Doctoral Studentship. Dr. Lillian DeBruin provided Fig. 4. We are grateful to many colleagues, past and present, but particularly Drs. Noboru Ishiyama, Ian Bates, and Christopher Hill whose work and ideas permeate this review in an unravellable way, and to Drs. Mario Moscarello and Joan Boggs (Hospital for Sick Children, Toronto) with whom we have collaborated rewardingly. Drs. Tony and Celia Campagnoni, University of California at Los Angeles, have always been an inspiration and support to us, for which we are grateful.


  1. 1.
    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 25:330–341PubMedGoogle Scholar
  2. 2.
    Bates IR, Harauz G (2003) Molecular dynamics exposes alpha-helices in myelin basic protein. J Mol Model (Online) 9:290–297Google Scholar
  3. 3.
    Curis E, Nicolis I, Moinard C, Osowska S, Zerrouk N, Benazeth S, Cynober L (2005) Almost all about citrulline in mammals. Amino Acids 29:177–205PubMedGoogle Scholar
  4. 4.
    Voet D, Voet JG (2004) Biochemistry. Wiley, New YorkGoogle Scholar
  5. 5.
    Ochoa JL, Porath J, Kempf J, Egly JM (1980) Electron donor-acceptor properties of urea and its role in charge-transfer chromatography. J Chromatogr 188:257–261Google Scholar
  6. 6.
    Mizutani Y, Kamogawa K, Nakanishi K (1989) Effect of urea on hydrophobic interaction - Raman difference spectroscopy on the C-H stretching vibration of acetone and the C-N stretching vibration of urea. J Phys Chem 93:5650–5654Google Scholar
  7. 7.
    Takahara K, Akashi K, Yokota A (2005) Purification and characterization of glutamate N-acetyltransferase involved in citrulline accumulation in wild watermelon. FEBS J 272:5353–5364PubMedGoogle Scholar
  8. 8.
    Legrain C, Stalon V, Noullez JP, Mercenier A, Simon JP, Broman K, Wiame JM (1977) Structure and function of ornithine carbamoyltransferases. Eur J Biochem 80:401–409PubMedGoogle Scholar
  9. 9.
    Iwanaga T, Yamazaki T, Kominami S (1999) Kinetic studies on the successive reaction of neuronal nitric oxide synthase from L-arginine to nitric oxide and L-citrulline. Biochemistry 38:16629–16635PubMedGoogle Scholar
  10. 10.
    Shibatani T, Kakimoto T, Chibata I (1975) Crystallization and properties of L-arginine deiminase of Pseudomonas putida. J Biol Chem 250:4580–4583PubMedGoogle Scholar
  11. 11.
    Smith DW, Ganaway RL, Fahrney DE (1978) Arginine deiminase from Mycoplasma arthritidis. Structure-activity relationships among substrates and competitive inhibitors. J Biol Chem 253:6016–6020PubMedGoogle Scholar
  12. 12.
    Zuniga M, Perez G, Gonzalez-Candelas F (2002) Evolution of arginine deiminase (ADI) pathway genes. Mol Phylogenet Evol 25:429–444PubMedGoogle Scholar
  13. 13.
    Lu X, Galkin A, Herzberg O, Dunaway-Mariano D (2004) Arginine deiminase uses an active-site cysteine in nucleophilic catalysis of L-arginine hydrolysis. J Am Chem Soc 126:5374–5375PubMedGoogle Scholar
  14. 14.
    Galkin A, Kulakova L, Sarikaya E, Lim K, Howard A, Herzberg O (2004) Structural insight into arginine degradation by arginine deiminase, an antibacterial and parasite drug target. J Biol Chem 279:14001–14008PubMedGoogle Scholar
  15. 15.
    Lu X, Li L, Wu R, Feng X, Li Z, Yang H, Wang C, Guo H, Galkin A, Herzberg O, Mariano PS, Martin BM, Dunaway-Mariano D (2006) Kinetic analysis of Pseudomonas aeruginosa arginine deiminase mutants and alternate substrates provides insight into structural determinants of function. Biochemistry 45:1162–1172PubMedGoogle Scholar
  16. 16.
    Gruening P, Fulde M, Valentin-Weigand P, Goethe R (2006) Structure, regulation, and putative function of the arginine deiminase system of Streptococcus suis. J Bacteriol 188:361–369PubMedGoogle Scholar
  17. 17.
    Ogawa T, Kimoto M, Sasaoka K (1989) Purification and properties of a new enzyme, NG,NG-dimethylarginine dimethylaminohydrolase, from rat kidney. J Biol Chem 264:10205–10209PubMedGoogle Scholar
  18. 18.
    Knipp M, Vasak M (2000) A colorimetric 96-well microtiter plate assay for the determination of enzymatically formed citrulline. Anal Biochem 286:257–264PubMedGoogle Scholar
  19. 19.
    Balandraud N, Gouret P, Danchin EG, Blanc M, Zinn D, Roudier J, Pontarotti P (2005) A rigorous method for multigenic families’ functional annotation: the peptidyl arginine deiminase (PADs) proteins family example. BMC Genomics 6:153PubMedGoogle Scholar
  20. 20.
    Vossenaar ER, Zendman AJ, van Venrooij WJ, Pruijn GJ (2003) PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. Bioessays 25:1106–1118PubMedGoogle Scholar
  21. 21.
    Arita K, Hashimoto H, Shimizu T, Yamada M, Sato M (2003) Crystallization and preliminary X-ray crystallographic analysis of human peptidylarginine deiminase V. Acta Crystallogr D Biol Crystallogr 59:2332–2333PubMedGoogle Scholar
  22. 22.
    Arita K, Hashimoto H, Shimizu T, Nakashima K, Yamada M, Sato M (2004) Structural basis for Ca(2+)-induced activation of human PAD4. Nat Struct Mol Biol 11:777–783PubMedGoogle Scholar
  23. 23.
    Kearney PL, Bhatia M, Jones NG, Yuan L, Glascock MC, Catchings KL, Yamada M, Thompson PR (2005) Kinetic characterization of protein arginine deiminase 4: a transcriptional corepressor implicated in the onset and progression of rheumatoid arthritis. Biochemistry 44:10570–10582PubMedGoogle Scholar
  24. 24.
    Nakayama-Hamada M, Suzuki A, Kubota K, Takazawa T, Ohsaka M, Kawaida R, Ono M, Kasuya A, Furukawa H, Yamada R, Yamamoto K (2005) Comparison of enzymatic properties between hPADI2 and hPADI4. Biochem Biophys Res Commun 327:192–200PubMedGoogle Scholar
  25. 25.
    Bannister AJ, Kouzarides T (2005) Reversing histone methylation. Nature 436:1103–1106PubMedGoogle Scholar
  26. 26.
    Woods AS (2004) The mighty arginine, the stable quaternary amines, the powerful aromatics, and the aggressive phosphate: their role in the noncovalent minuet. J Proteome Res 3:478–484PubMedGoogle Scholar
  27. 27.
    Woods AS, Ferre S (2005) Amazing stability of the arginine-phosphate electrostatic interaction. J Proteome Res 4:1397–1402PubMedGoogle Scholar
  28. 28.
    van Venrooij WJ, Pruijn GJ (2000) Citrullination: a small change for a protein with great consequences for rheumatoid arthritis. Arthritis Res 2:249–251PubMedGoogle Scholar
  29. 29.
    György B, Tóth E, Tarcsa E, Falus A, Buzás EI (2006) Citrullination: a posttranslational modification in health and disease. Int J Biochem Cell Biol 38:1662–1677PubMedGoogle Scholar
  30. 30.
    Harauz G, Ishiyama N, Hill CMD, Bates IR, Libich DS, Farès C (2004) Myelin basic protein-diverse conformational states of an intrinsically unstructured protein and its roles in myelin assembly and multiple sclerosis. Micron 35:503–542PubMedGoogle Scholar
  31. 31.
    Boggs JM (2006) Myelin basic protein: a multifunctional protein. Cell Mol Life Sci 63 (In press)Google Scholar
  32. 32.
    Moscarello MA, Mastronardi F, Wood DD (2006) The role of citrullinated proteins suggests a novel mechanism in the pathogenesis of multiple sclerosis. Neurochem Res (This issue)Google Scholar
  33. 33.
    Curran JF (2003) Death, taxes, and the genetic code? Chem Biol 10:586–587PubMedGoogle Scholar
  34. 34.
    Ishiyama N, Bates IR, Hill CMD, 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 136:30–45PubMedGoogle Scholar
  35. 35.
    Hill CMD, Bates IR, White GF, Hallett FR, Harauz G (2002) Effects of the osmolyte trimethylamine-N-oxide on conformation, self-association, and two-dimensional crystallization of myelin basic protein. J Struct Biol 139:13–26PubMedGoogle Scholar
  36. 36.
    Ishiyama N, Hill CMD, Bates IR, Harauz G (2002) The formation of helical tubular vesicles by binary monolayers containing a nickel-chelating lipid and phosphoinositides in the presence of basic polypeptides. Chem Phys Lipids 114:103–111PubMedGoogle Scholar
  37. 37.
    Libich DS, Hill CMD, Bates IR, Hallett FR, Armstrong S, Siemiarczuk A, Harauz G (2003) Interaction of the 18.5-kDa 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 12:1507–1521PubMedGoogle Scholar
  38. 38.
    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 148:353–369PubMedGoogle Scholar
  39. 39.
    Kroner PA, Friedman KD, Fahs SA, Scott JP, Montgomery RR (1991) Abnormal binding of factor VIII is linked with the substitution of glutamine for arginine 91 in von Willebrand factor in a variant form of von Willebrand disease. J Biol Chem 266:19146–19149PubMedGoogle Scholar
  40. 40.
    Durovic S, Mrz W, Frank S, Scharnagl H, Baumstark MW, Zechner R, Kostner GM (1994) Decreased binding of apolipoprotein (a) to familial defective apolipoprotein B-100 (Arg3500→Gln). A study of the assembly of recombinant apolipoprotein (a) with mutant low density lipoproteins. J Biol Chem 269:30320–30325PubMedGoogle Scholar
  41. 41.
    Kishimoto M, Hashiramoto M, Yonezawa K, Shii K, Kazumi T, Kasuga M (1994) Substitution of glutamine for arginine 1131. A newly identified mutation in the catalytic loop of the tyrosine kinase domain of the human insulin receptor. J Biol Chem 269:11349–11355PubMedGoogle Scholar
  42. 42.
    Baumann N, Pham-Dinh D (2001) Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev 81:871–927PubMedGoogle Scholar
  43. 43.
    Trapp BD, Kidd GJ (2004) Structure of the myelinated axon. In: Lazzarini RA, Griffin JW, Lassman H, Nave K-A, Miller RH, Trapp BD (eds) Myelin biology and disorders. Elsevier Academic Press, San Diego, pp 3–27Google Scholar
  44. 44.
    Pribyl TM, Campagnoni CW, Kampf K, Kashima T, Handley VW, McMahon J, Campagnoni AT (1993) The human myelin basic protein gene is included within a 179-kilobase transcription unit: expression in the immune and central nervous systems. Proc Natl Acad Sci USA 90:10695–10699PubMedGoogle Scholar
  45. 45.
    Campagnoni AT, Pribyl TM, Campagnoni CW, Kampf K, Amur-Umarjee S, Landry CF, Handley VW, Newman SL, Garbay B, Kitamura K (1993) Structure and developmental regulation of Golli-mbp, a 105-kilobase gene that encompasses the myelin basic protein gene and is expressed in cells in the oligodendrocyte lineage in the brain. J Biol Chem 268:4930–4938PubMedGoogle Scholar
  46. 46.
    Campagnoni AT, Campagnoni C (2004) Myelin basic protein gene. In: Lazzarini RA, Griffin JW, Lassman H, Nave K-A, Miller RH, Trapp BD (eds) Myelin biology and disorders. Elsevier Academic Press, San Diego, pp 387–400Google Scholar
  47. 47.
    Landry CF, Ellison JA, Pribyl TM, Campagnoni C, Kampf K, Campagnoni AT (1996) Myelin basic protein gene expression in neurons: developmental and regional changes in protein targeting within neuronal nuclei, cell bodies, and processes. J Neurosci 16:2452–2462PubMedGoogle Scholar
  48. 48.
    Givogri MI, Bongarzone ER, Schonmann V, Campagnoni AT (2001) Expression and regulation of golli products of myelin basic protein gene during in vitro development of oligodendrocytes. J Neurosci Res 66:679–690PubMedGoogle Scholar
  49. 49.
    Farhadi HF, Lepage P, Forghani R, Friedman HC, Orfali W, Jasmin L, Miller W, Hudson TJ, Peterson AC (2003) A combinatorial network of evolutionarily conserved myelin basic protein regulatory sequences confers distinct glial-specific phenotypes. J Neurosci 23:10214–10223PubMedGoogle Scholar
  50. 50.
    Farhadi HF, Peterson AC (2006) The myelin basic protein gene: a prototype for combinatorial mammalian transcriptional regulation. Adv Neurol 98:65–76PubMedGoogle Scholar
  51. 51.
    Brady GW, Murthy NS, Fein DB, Wood DD, Moscarello MA (1981) The effect of basic myelin protein on multilayer membrane formation. Biophys J 34:345–350PubMedGoogle Scholar
  52. 52.
    Sedzik J, Blaurock AE, Hochli M (1984) Lipid/myelin basic protein multilayers. A model for the cytoplasmic space in central nervous system myelin. J Mol Biol 174:385–409PubMedGoogle Scholar
  53. 53.
    Hu Y, Doudevski I, Wood DD, Moscarello MA, Husted C, Genain C, Zasadzinski JA, Israelachvili J (2004) Synergistic interactions of lipids and myelin basic protein. Proc Natl Acad Sci USA 101:13466–13471PubMedGoogle Scholar
  54. 54.
    Cristofolini L, Fontana MP, Serra F, Fasano A, Riccio P, Konovalov O (2005) Microstructural analysis of the effects of incorporation of myelin basic protein in phospholipid layers. Eur Biophys J 34:1041–1048PubMedGoogle Scholar
  55. 55.
    Bates IR, Feix JB, Boggs JM, Harauz G (2004) An immunodominant epitope of myelin basic protein is an amphipathic alpha-helix. J Biol Chem 279:5757–5764PubMedGoogle Scholar
  56. 56.
    Musse AA, Boggs JM, Harauz G (2006) Deimination of membrane-bound myelin basic protein in multiple sclerosis exposes an immunodominant epitope. Proc Natl Acad Sci USA 103:4422–4427PubMedGoogle Scholar
  57. 57.
    Bates IR, Boggs JM, Feix JB, Harauz G (2003) Membrane-anchoring and charge effects in the interaction of myelin basic protein with lipid bilayers studied by site-directed spin labeling. J Biol Chem 278:29041–29047PubMedGoogle Scholar
  58. 58.
    Wood DD, Moscarello MA (1997) Myelin basic protein – the implication of post-translational changes for demyelinating disease. In: Russell WC (eds) Molecular biology of multiple sclerosis. Wiley, New York, pp 37–54Google Scholar
  59. 59.
    Martenson RE, Gaitonde M (1969) Comparative studies of highly basic proteins of ox brain and rat brain. Microheterogeneity of basic encephalitogenic (myelin) protein. J Neurochem 16:889–898PubMedGoogle Scholar
  60. 60.
    Martenson RE, Gaitonde MK (1969) Electrophoretic analysis of the highly basic proteins of the rat brain fraction which induces experimental allergic encephalomyelitis. J Neurochem 16:333–347PubMedGoogle Scholar
  61. 61.
    Chou FC, Chou CH, Shapira R, Kibler RF (1976) Basis of microheterogeneity of myelin basic protein. J Biol Chem 251:2671–2679PubMedGoogle Scholar
  62. 62.
    Cheifetz S, Moscarello MA, Deber CM (1984) NMR investigation of the charge isomers of bovine myelin basic protein. Arch Biochem Biophys 233:151–160PubMedGoogle Scholar
  63. 63.
    Fannon AM, Moscarello MA (1991) Characterization of myelin basic protein charge isomers from adult mouse brain. Neuroreport 2:135–138PubMedGoogle Scholar
  64. 64.
    Boulias C, Pang H, Mastronardi F, Moscarello MA (1995) The isolation and characterization of four myelin basic proteins from the unbound fraction during CM52 chromatography. Arch Biochem Biophys 322:174–182PubMedGoogle Scholar
  65. 65.
    Wood DD, McLaurin J, Moscarello MA (1990) A hydroxyproline-containing protein from shark brain that is related to myelin basic protein. J Neurochem 55:1697–1702PubMedGoogle Scholar
  66. 66.
    Mastronardi FG, Boulias C, Roots BI, Moscarello MA (1993) Characterization of basic proteins from goldfish myelin. J Neurochem 60:153–160PubMedGoogle Scholar
  67. 67.
    Zand R, Jin X, Kim J, Wall DB, Gould R, Lubman DM (2001) Studies of posttranslational modifications in spiny dogfish myelin basic protein. Neurochem Res 26:539–547PubMedGoogle Scholar
  68. 68.
    Wood DD, She YM, Freer AD, Harauz G, Moscarello MA (2002) Primary structure of equine myelin basic protein by mass spectrometry. Arch Biochem Biophys 405:137–146PubMedGoogle Scholar
  69. 69.
    Zand R, Li MX, Jin X, Lubman D (1998) Determination of the sites of posttranslational modifications in the charge isomers of bovine myelin basic protein by capillary electrophoresis-mass spectroscopy. Biochemistry 37:2441–2449PubMedGoogle Scholar
  70. 70.
    Kim JK, Mastronardi FG, Wood DD, Lubman DM, Zand R, Moscarello MA (2003) Multiple sclerosis: an important role for post-translational modifications of myelin basic protein in pathogenesis. Mol Cell Proteomics 2:453–462PubMedGoogle Scholar
  71. 71.
    Wood DD, Moscarello MA (1989) The isolation, characterization, and lipid-aggregating properties of a citrulline containing myelin basic protein. J Biol Chem 264:5121–5127PubMedGoogle Scholar
  72. 72.
    Koshy KM, Boggs JM (1993) Interference of carbohydrates in the quantitation of protein-bound citrulline by amino acid analysis. Anal Biochem 208:375–381PubMedGoogle Scholar
  73. 73.
    Yang XJ (2005) Multisite protein modification and intramolecular signaling. Oncogene 24:1653–1662PubMedGoogle Scholar
  74. 74.
    Martenson RE (1980) Myelin basic protein: what does it do? In: Kumar S (eds) Biochemistry of brain. Pergamon, Oxford, pp 49–79Google Scholar
  75. 75.
    Campagnoni AT, Skoff RP (2001) The pathobiology of myelin mutants reveal novel biological functions of the MBP and PLP genes. Brain Pathol 11:74–91PubMedCrossRefGoogle Scholar
  76. 76.
    Lassmann H (2004) Cellular damage and repair in multiple sclerosis. In: Lazzarini RA, Griffin JW, Lassman H, Nave K-A, Miller RH, Trapp BD (eds) Myelin biology and disorders. Elsevier Academic Press, San Diego, pp 733–762Google Scholar
  77. 77.
    Ferguson B, Matyszak MK, Esiri MM, Perry VH (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120:393–399PubMedGoogle Scholar
  78. 78.
    Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278–285PubMedGoogle Scholar
  79. 79.
    Lutton JD, Winston R, Rodman TC (2004) Multiple sclerosis: etiological mechanisms and future directions. Exp Biol Med (Maywood) 229:12–20Google Scholar
  80. 80.
    Compston A (2004) Genetic susceptibility and epidemiology. In: Lazzarini RA, Griffin JW, Lassman H, Nave K-A, Miller RH, Trapp BD (eds) Myelin biology and disorders. Elsevier Academic Press, San Diego, pp 701–731Google Scholar
  81. 81.
    Sospedra M, Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol 23:683–747PubMedGoogle Scholar
  82. 82.
    Ibrahim SM, Gold R (2005) Genomics, proteomics, metabolomics: what is in a word for multiple sclerosis? Curr Opin Neurol 18:231–235PubMedGoogle Scholar
  83. 83.
    Oksenberg JR, Barcellos LF (2005) Multiple sclerosis genetics: leaving no stone unturned. Genes Immun 6:375–387PubMedGoogle Scholar
  84. 84.
    Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H (1999) A quantitative analysis of oligodendrocytes in multiple sclerosis lesions. A study of 113 cases. Brain 122:2279–2295PubMedGoogle Scholar
  85. 85.
    Lassmann H, Bruck W, Lucchinetti C (2001) Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol Med 7:115–121PubMedGoogle Scholar
  86. 86.
    Lublin FD (2004) Multiple sclerosis classification and overview. In: Lazzarini RA, Griffin JW, Lassman H, Nave K-A, Miller RH, Trapp BD (eds) Myelin biology and disorders. Elsevier Academic Press, San Diego, pp 691–699Google Scholar
  87. 87.
    John GR, Shankar SL, Shafit-Zagardo B, Massimi A, Lee SC, Raine CS, Brosnan CF (2002) Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nat Med 8:1115–1121PubMedGoogle Scholar
  88. 88.
    Franklin RJ (2002) Why does remyelination fail in multiple sclerosis? Nat Rev Neurosci 3:705–714PubMedGoogle Scholar
  89. 89.
    Makhlouf K, Imitola J, Khoury SJ (2002) Experimental autoimmune encephalomyelitis and multiple sclerosis: from bench to bedside. In: Dangond F (ed) Disorders of myelin in the central and peripheral nervous systems. Butterworth/ Heinemann, Woburn, pp 155–164Google Scholar
  90. 90.
    Barnett MH, Prineas JW (2004) Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 55:458–468PubMedGoogle Scholar
  91. 91.
    Chaudhuri A, Behan PO (2005) Multiple sclerosis: looking beyond autoimmunity. J R Soc Med 98:303–306PubMedGoogle Scholar
  92. 92.
    Simons-Johnson R, Roder JC, Riordan JR (1995) Over-expression of the DM-20 myelin proteolipid causes central nervous system demyelination in transgenic mice. J Neurochem 64:967–976CrossRefGoogle Scholar
  93. 93.
    Mastronardi FG, Ackerley CA, Arsenault L, Roots BI, Moscarello MA (1993) Demyelination in a transgenic mouse: a model for multiple sclerosis. J Neurosci Res 36:315–324PubMedGoogle Scholar
  94. 94.
    Barrese N, Mak B, Fisher L, Moscarello MA (1998) Mechanism of demyelination in DM20 transgenic mice involves increased fatty acylation. J Neurosci Res 53:143–152PubMedGoogle Scholar
  95. 95.
    Mastronardi FG, Al Sabbagh A, Nelson PA, Rego J, Roots BI, Moscarello MA (1996) Myelin basic protein in experimental allergic encephalomyelitis is not affected at the posttranslational level: implications for demyelinating disease. J Neurosci Res 44:344–349PubMedGoogle Scholar
  96. 96.
    Mastronardi FG, Ackerley CA, Roots BI, Moscarello MA (1996) Loss of myelin basic protein cationicity in DM20 transgenic mice is dosage dependent. J Neurosci Res 44:301–307PubMedGoogle Scholar
  97. 97.
    Mastronardi FG, Mak B, Ackerley CA, Roots BI, Moscarello MA (1996) Modifications of myelin basic protein in DM20 transgenic mice are similar to those in myelin basic protein from multiple sclerosis. J Clin Invest 97:349–358PubMedGoogle Scholar
  98. 98.
    Moscarello MA (1997) Myelin basic protein, the “executive” molecule of the myelin membrane. In: Juurlink BHJ, Devon RM, Doucette JR, Nazarali AJ, Schreyer DJ, Verge VMK (eds) Cell biology and pathology of myelin: evolving biological concepts and therapeutic approaches. Plenum Press, New York, pp 13–25Google Scholar
  99. 99.
    Finch PR, Wood DD, Moscarello MA (1971) The presence of citrulline in a myelin protein fraction. FEBS Lett 15:145–148PubMedGoogle Scholar
  100. 100.
    Moscarello MA, Wood DD, Ackerley C, Boulias C (1994) Myelin in multiple sclerosis is developmentally immature. J Clin Invest 94:146–154PubMedGoogle Scholar
  101. 101.
    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 40:18–24PubMedGoogle Scholar
  102. 102.
    Whitaker JN, Mitchell GW (1996) A possible role for altered myelin basic protein in multiple sclerosis. Ann Neurol 40:3–4PubMedGoogle Scholar
  103. 103.
    Wood DD, Moscarello MA (1984) Is the myelin membrane abnormal in multiple sclerosis? J Membr Biol 79:195–201PubMedGoogle Scholar
  104. 104.
    Martin R, Whitaker JN, Rhame L, Goodin RR, McFarland HF (1994) Citrulline-containing myelin basic protein is recognized by T-cell lines derived from multiple sclerosis patients and healthy individuals. Neurology 44:123–129PubMedGoogle Scholar
  105. 105.
    Tranquill LR, Cao L, Ling NC, Kalbacher H, Martin RM, Whitaker JN (2000) Enhanced T cell responsiveness to citrulline-containing myelin basic protein in multiple sclerosis patients. Mult Scler 6:220–225PubMedGoogle Scholar
  106. 106.
    Ursell MR, McLaurin J, Wood DD, Ackerley CA, Moscarello MA (1995) Localization and partial characterization of a 60 kDa citrulline-containing transport form of myelin basic protein from MO3–13 cells and human white matter. J Neurosci Res 42:41–53PubMedGoogle Scholar
  107. 107.
    Fannon AM, Moscarello MA (1990) Myelin basic protein is affected by reduced synthesis of myelin proteolipid protein in the jimpy mouse. Biochem J 268:105–110PubMedGoogle Scholar
  108. 108.
    Akiyama K, Sakurai Y, Asou H, Senshu T (1999) Localization of peptidylarginine deiminase type II in a stage-specific immature oligodendrocyte from rat cerebral hemisphere. Neurosci Lett 274:53–55PubMedGoogle Scholar
  109. 109.
    Seiwa C, Sugiyama I, Yagi T, Iguchi T, Asou H (2000) Fyn tyrosine kinase participates in the compact myelin sheath formation in the central nervous system. Neurosci Res 37:21–31PubMedGoogle Scholar
  110. 110.
    Sambandam T, Belousova M, Accaviti-Loper MA, Blanquicett C, Guercello V, Raijmakers R, Nicholas AP (2004) Increased peptidylarginine deiminase type II in hypoxic astrocytes. Biochem Biophys Res Commun 325:1324–1329PubMedGoogle Scholar
  111. 111.
    Nicholas AP, Sambandam T, Echols JD, Barnum SR (2005) Expression of citrullinated proteins in murine experimental autoimmune encephalomyelitis. J Comp Neurol 486:254–266PubMedGoogle Scholar
  112. 112.
    Raijmakers R, Vogelzangs J, Croxford JL, Wesseling P, van Venrooij WJ, Pruijn GJ (2005) Citrullination of central nervous system proteins during the development of experimental autoimmune encephalomyelitis. J Comp Neurol 486:243–253PubMedGoogle Scholar
  113. 113.
    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 80:120–128PubMedGoogle Scholar
  114. 114.
    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 47:2508–2514PubMedGoogle Scholar
  115. 115.
    Nicholas AP, Sambandam T, Echols JD, Tourtellotte WW (2004) Increased citrullinated glial fibrillary acidic protein in secondary progressive multiple sclerosis. J Comp Neurol 473:128–136PubMedGoogle Scholar
  116. 116.
    Kubilus J, Baden HP (1983) Purification and properties of a brain enzyme which deiminates proteins. Biochim Biophys Acta 745:285–291PubMedGoogle Scholar
  117. 117.
    Takahara H, Koyama M, Sugawara K (1987) Subcellular location of peptidylarginine deiminase in the mouse brain. Agric Biol Chem 51:1471–1473Google Scholar
  118. 118.
    Vincent SR, Leung E, Watanabe K (1992) Immunohistochemical localization of peptidylarginine deiminase in the rat brain. J Chem Neuroanat 5:159–168PubMedGoogle Scholar
  119. 119.
    Lamensa JW, Moscarello MA (1993) Deimination of human myelin basic protein by a peptidylarginine deiminase from bovine brain. J Neurochem 61:987–996PubMedGoogle Scholar
  120. 120.
    Pritzker LB, Nguyen TA, Moscarello MA (1999) The developmental expression and activity of peptidylarginine deiminase in the mouse. Neurosci Lett 266:161–164PubMedGoogle Scholar
  121. 121.
    Moscarello MA, Pritzker L, Mastronardi FG, Wood DD (2002) Peptidylarginine deiminase: a candidate factor in demyelinating disease. J Neurochem 81:335–343PubMedGoogle Scholar
  122. 122.
    Mastronardi FG, Moscarello MA (2005) Molecules affecting myelin stability: a novel hypothesis regarding the pathogenesis of multiple sclerosis. J Neurosci Res 80:301–308PubMedGoogle Scholar
  123. 123.
    Mastronardi FG, Wood DD, Mei J, Raijmakers R, Tseveleki V, Dosch H-M, Probert L, Casaccia-Bonnefil P, Moscarello MA (2006) Increased citrullination of histone H3 in MS brain and animal models for demyelination: A role for TNF-induced PAD4 translocation. J Neurosci (Submitted)Google Scholar
  124. 124.
    De Keyser J, Schaaf M, Teelken A (1999) Peptidylarginine deiminase activity in postmortem white matter of patients with multiple sclerosis. Neurosci Lett 260:74–76PubMedGoogle Scholar
  125. 125.
    Takahara H, Oikawa Y, Sugawara K (1983) Purification and characterization of peptidylarginine deiminase from rabbit skeletal muscle. J Biochem (Tokyo) 94:1945–1953Google Scholar
  126. 126.
    Watanabe K, Akiyama K, Hikichi K, Ohtsuka R, Okuyama A, Senshu T (1988) Combined biochemical and immunochemical comparison of peptidylarginine deiminases present in various tissues. Biochim Biophys Acta 966:375–383PubMedGoogle Scholar
  127. 127.
    Nomura K (1992) Specificity and mode of action of the muscle-type protein-arginine deiminase. Arch Biochem Biophys 293:362–369PubMedGoogle Scholar
  128. 128.
    Senshu T, Kan S, Ogawa H, Manabe M, Asaga H (1996) Preferential deimination of keratin K1 and filaggrin during the terminal differentiation of human epidermis. Biochem Biophys Res Commun 225:712–719PubMedGoogle Scholar
  129. 129.
    Tarcsa E, Marekov LN, Mei G, Melino G, Lee SC, Steinert PM (1996) Protein unfolding by peptidylarginine deiminase. Substrate specificity and structural relationships of the natural substrates trichohyalin and filaggrin. J Biol Chem 271:30709–30716PubMedGoogle Scholar
  130. 130.
    Tarcsa E, Marekov LN, Andreoli J, Idler WW, Candi E, Chung SI, Steinert PM (1997) The fate of trichohyalin. Sequential post-translational modifications by peptidyl-arginine deiminase and transglutaminases. J Biol Chem 272:27893–27901PubMedGoogle Scholar
  131. 131.
    Mizoguchi M, Manabe M, Kawamura Y, Kondo Y, Ishidoh K, Kominami E, Watanabe K, Asaga H, Senshu T, Ogawa H (1998) Deimination of 70-kD nuclear protein during epidermal apoptotic events in vitro. J Histochem Cytochem 46:1303–1309PubMedGoogle Scholar
  132. 132.
    Takai Y, Ogawara M, Tomono Y, Moritoh C, Imajoh-Ohmi S, Tsutsumi O, Taketani Y, Inagaki M (1996) Mitosis-specific phosphorylation of vimentin by protein kinase C coupled with reorganization of intracellular membranes. J Cell Biol 133:141–149PubMedGoogle Scholar
  133. 133.
    Asaga H, Yamada M, Senshu T (1998) Selective deimination of vimentin in calcium ionophore-induced apoptosis of mouse peritoneal macrophages. Biochem Biophys Res Commun 243:641–646PubMedGoogle Scholar
  134. 134.
    Vossenaar ER, Zendman AJ, van Venrooij WJ (2004) Citrullination, a possible functional link between susceptibility genes and rheumatoid arthritis. Arthritis Res Ther 6:1–5PubMedGoogle Scholar
  135. 135.
    Lundberg K, Nijenhuis S, Vossenaar ER, Palmblad K, van Venrooij WJ, Klareskog L, Zendman AJ, Harris HE (2005) Citrullinated proteins have increased immunogenicity and arthritogenicity and their presence in arthritic joints correlates with disease severity. Arthritis Res Ther 7:R458–R467PubMedGoogle Scholar
  136. 136.
    Vossenaar ER, Robinson WH (2005) Citrullination and autoimmune disease: 8th Bertine Koperberg meeting. Ann Rheum Dis 64:1513–1515PubMedGoogle Scholar
  137. 137.
    Schellekens GA, de Jong BA, van den Hoogen FH, van de Putte LB, van Venrooij WJ (1998) Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest 101:273–281PubMedCrossRefGoogle Scholar
  138. 138.
    Girbal-Neuhauser E, Durieux JJ, Arnaud M, Dalbon P, Sebbag M, Vincent C, Simon M, Senshu T, Masson-Bessière C, Jolivet-Reynaud C, Jolivet M, Serre G (1999) The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues. J Immunol 162:585–594PubMedGoogle Scholar
  139. 139.
    Masson-Bessière C, Sebbag M, Girbal-Neuhauser E, Nogueira L, Vincent C, Senshu T, Serre G (2001) The major synovial targets of the rheumatoid arthritis-specific antifilaggrin autoantibodies are deiminated forms of the alpha- and beta-chains of fibrin. J Immunol 166:4177–4184PubMedGoogle Scholar
  140. 140.
    Hill J, Cairns E, Bell DA (2004) The joy of citrulline: new insights into the diagnosis, pathogenesis, and treatment of rheumatoid arthritis. J Rheumatol 31:1471–1473PubMedGoogle Scholar
  141. 141.
    Nijenhuis S, Zendman AJ, Vossenaar ER, Pruijn GJ, van Venrooij WJ (2004) Autoantibodies to citrullinated proteins in rheumatoid arthritis: clinical performance and biochemical aspects of an RA-specific marker. Clin Chim Acta 350:17–34PubMedGoogle Scholar
  142. 142.
    Vossenaar ER, Despres N, Lapointe E, van der HA, Lora M, Senshu T, van Venrooij WJ, Menard HA (2004) Rheumatoid arthritis specific anti-Sa antibodies target citrullinated vimentin. Arthritis Res Ther 6:R142–R150PubMedGoogle Scholar
  143. 143.
    Vossenaar ER, van Venrooij WJ (2004) Citrullinated proteins: sparks that may ignite the fire in rheumatoid arthritis. Arthritis Res Ther 6:107–111PubMedGoogle Scholar
  144. 144.
    Zendman AJ, Vossenaar ER, van Venrooij WJ (2004) Autoantibodies to citrullinated (poly)peptides: a key diagnostic and prognostic marker for rheumatoid arthritis. Autoimmunity 37:295–299PubMedGoogle Scholar
  145. 145.
    Yamada R (2005) Peptidylarginine deiminase type 4, anticitrullinated peptide antibodies, and rheumatoid arthritis. Autoimmun Rev 4:201–206PubMedGoogle Scholar
  146. 146.
    Migliorini P, Pratesi F, Tommasi C, Anzilotti C (2005) The immune response to citrullinated antigens in autoimmune diseases. Autoimmun Rev 4:561–564PubMedGoogle Scholar
  147. 147.
    Yamada R, Suzuki A, Chang X, Yamamoto K (2003) Peptidylarginine deiminase type 4: identification of a rheumatoid arthritis-susceptible gene. Trends Mol Med 9:503–508PubMedGoogle Scholar
  148. 148.
    Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, Nagasaki M, Nakayama-Hamada M, Kawaida R, Ono M, Ohtsuki M, Furukawa H, Yoshino S, Yukioka M, Tohma S, Matsubara T, Wakitani S, Teshima R, Nishioka Y, Sekine A, Iida A, Takahashi A, Tsunoda T, Nakamura Y, Yamamoto K (2003) Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 34:395–402PubMedGoogle Scholar
  149. 149.
    Chang X, Yamada R, Sawada T, Suzuki A, Kochi Y, Yamamoto K (2005) The inhibition of antithrombin by peptidylarginine deiminase 4 may contribute to pathogenesis of rheumatoid arthritis. Rheumatology (Oxford) 44:293–298Google Scholar
  150. 150.
    Chang X, Yamada R, Suzuki A, Sawada T, Yoshino S, Tokuhiro S, Yamamoto K (2005) Localization of peptidylarginine deiminase 4 (PADI4) and citrullinated protein in synovial tissue of rheumatoid arthritis. Rheumatology (Oxford) 44:40–50Google Scholar
  151. 151.
    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 44:13744–13752PubMedGoogle Scholar
  152. 152.
    Luo Y, Knuckley B, Lee YH, Stallcup MR, Thompson PR (2006) A fluoroacetamidine-based inactivator of protein arginine deiminase 4: design, synthesis, and in vitro and in vivo evaluation. J Am Chem Soc 128:1092–1093PubMedGoogle Scholar
  153. 153.
    Doyle HA, Mamula MJ (2001) Post-translational protein modifications in antigen recognition and autoimmunity. Trends Immunol 22:443–449PubMedGoogle Scholar
  154. 154.
    Doyle HA, Mamula MJ (2002) Posttranslational protein modifications: new flavors in the menu of autoantigens. Curr Opin Rheumatol 14:244–249PubMedGoogle Scholar
  155. 155.
    Doyle HA, Mamula MJ (2005) Posttranslational modifications of self-antigens. Ann N Y Acad Sci 1050:1–9PubMedGoogle Scholar
  156. 156.
    Moscarello MA (1990) Myelin basic protein: a dynamically changing structure. Prog Clin Biol Res 336:25–48PubMedGoogle Scholar
  157. 157.
    Wright PE, Dyson HJ (1999) Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm. J Mol Biol 293:321–331PubMedGoogle Scholar
  158. 158.
    Uversky VN, Gillespie JR, Fink AL (2000) Why are “natively unfolded” proteins unstructured under physiologic conditions? Proteins 41:415–427PubMedGoogle Scholar
  159. 159.
    Dunker AK, Brown CJ, Lawson JD, Iakoucheva LM, Obradovic Z (2002) Intrinsic disorder and protein function. Biochemistry 41:6573–6582PubMedGoogle Scholar
  160. 160.
    Fink AL (2005) Natively unfolded proteins. Curr Opin Struct Biol 15:35–41PubMedGoogle Scholar
  161. 161.
    Receveur-Bréchot V, Bourhis JM, Uversky VN, Canard B, Longhi S (2006) Assessing protein disorder and induced folding. Proteins 62:24–45PubMedGoogle Scholar
  162. 162.
    Ward JJ, Sodhi JS, McGuffin LJ, Buxton BF, Jones DT (2004) Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. J Mol Biol 337:635–645PubMedGoogle Scholar
  163. 163.
    Tompa P (2002) Intrinsically unstructured proteins. Trends Biochem Sci 27:527–533PubMedGoogle Scholar
  164. 164.
    Tompa P, Szasz C, Buday L (2005) Structural disorder throws new light on moonlighting. Trends Biochem Sci 30:484–489PubMedGoogle Scholar
  165. 165.
    Tompa P (2005) The interplay between structure and function in intrinsically unstructured proteins. FEBS Lett 579:3346–3354PubMedGoogle Scholar
  166. 166.
    Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN (2005) Flexible nets. The roles of intrinsic disorder in protein interaction networks. FEBS J 272:5129–5148PubMedGoogle Scholar
  167. 167.
    Patil A, Nakamura H (2006) Disordered domains and high surface charge confer hubs with the ability to interact with multiple proteins in interaction networks. FEBS Lett 580:2041–2045PubMedGoogle Scholar
  168. 168.
    Shoemaker BA, Portman JJ, Wolynes PG (2000) Speeding molecular recognition by using the folding funnel: the fly-casting mechanism. Proc Natl Acad Sci USA 97:8868–8873PubMedGoogle Scholar
  169. 169.
    Gunasekaran K, Tsai CJ, Kumar S, Zanuy D, Nussinov R (2003) Extended disordered proteins: targeting function with less scaffold. Trends Biochem Sci 28:81–85PubMedGoogle Scholar
  170. 170.
    Fuxreiter M, Simon I, Friedrich P, Tompa P (2004) Preformed structural elements feature in partner recognition by intrinsically unstructured proteins. J Mol Biol 338:1015–1026PubMedGoogle Scholar
  171. 171.
    Oldfield CJ, Cheng Y, Cortese MS, Romero P, Uversky VN, Dunker AK (2005) Coupled folding and binding with alpha-helix-forming molecular recognition elements. Biochemistry 44:12454–12470PubMedGoogle Scholar
  172. 172.
    Dyson HJ, Wright PE (2002) Coupling of folding and binding for unstructured proteins. Curr Opin Struct Biol 12:54–60PubMedGoogle Scholar
  173. 173.
    Cao L, Goodin R, Wood D, Moscarello MA, Whitaker JN (1999) Rapid release and unusual stability of immunodominant peptide 45–89 from citrullinated myelin basic protein. Biochemistry 38:6157–6163PubMedGoogle Scholar
  174. 174.
    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 1:48–51PubMedGoogle Scholar
  175. 175.
    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 39:5374–5381PubMedGoogle Scholar
  176. 176.
    Pritzker LB, Joshi S, Harauz G, Moscarello MA (2000) Deimination of myelin basic protein. 2. Effect of methylation of MBP on its deimination by peptidylarginine deiminase. Biochemistry 39:5382–5388PubMedGoogle Scholar
  177. 177.
    D’Souza CA, Wood DD, She YM, Moscarello MA (2005) Autocatalytic cleavage of myelin basic protein: an alternative to molecular mimicry. Biochemistry 44:12905–12913PubMedGoogle Scholar
  178. 178.
    Moscarello MA, Pang H, Pace-Asciak CR, Wood DD (1992) The N-terminus of human myelin basic protein consists of C2, C4, C6, and C8 alkyl carboxylic acids. J Biol Chem 267:9779–9782PubMedGoogle Scholar
  179. 179.
    Boulias C, Moscarello MA (1994) ADP-ribosylation of human myelin basic protein. J Neurochem 63:351–359PubMedCrossRefGoogle Scholar
  180. 180.
    Bates IR, Matharu P, Ishiyama N, Rochon D, Wood DD, Polverini E, Moscarello MA, Viner NJ, Harauz G (2000) Characterization of a recombinant murine 18.5-kDa myelin basic protein. Protein Expr Purif 20:285–299PubMedGoogle Scholar
  181. 181.
    Brady GW, Fein DB, Wood DD, Moscarello MA (1981) The interaction of basic proteins from normal and multiple sclerosis myelin with phosphatidylglycerol vesicles. FEBS Lett 125:159–160PubMedGoogle Scholar
  182. 182.
    Brady GW, Fein DB, Wood DD, Moscarello MA (1985) The role of charge microheterogeneity of human myelin basic protein in the formation of phosphatidylglycerol multilayers. Biochem Biophys Res Commun 126:1161–1165PubMedGoogle Scholar
  183. 183.
    Cheifetz S, Boggs JM, Moscarello MA (1985) Increase in vesicle permeability mediated by myelin basic protein: effect of phosphorylation of basic protein. Biochemistry 24:5170–5175PubMedGoogle Scholar
  184. 184.
    Cheifetz S, Moscarello MA (1985) Effect of bovine basic protein charge microheterogeneity on protein-induced aggregation of unilamellar vesicles containing a mixture of acidic and neutral phospholipids. Biochemistry 24:1909–1914PubMedGoogle Scholar
  185. 185.
    Moscarello MA, Chia LS, Leighton D, Absolom D (1985) Size and surface charge properties of myelin vesicles from normal and diseased (multiple sclerosis) brain. J Neurochem 45:415–421PubMedGoogle Scholar
  186. 186.
    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 245:455–463PubMedGoogle Scholar
  187. 187.
    Moscarello MA, Brady GW, Fein DB, Wood DD, Cruz TF (1986) The role of charge microheterogeneity of basic protein in the formation and maintenance of the multilayered structure of myelin: a possible role in multiple sclerosis. J Neurosci Res 15:87–99PubMedGoogle Scholar
  188. 188.
    Jo E, Boggs JM (1995) Aggregation of acidic lipid vesicles by myelin basic protein: dependence on potassium concentration. Biochemistry 34:13705–13716PubMedGoogle Scholar
  189. 189.
    Boggs JM, Yip PM, Rangaraj G, Jo E (1997) Effect of posttranslational modifications to myelin basic protein on its ability to aggregate acidic lipid vesicles. Biochemistry 36:5065–5071PubMedGoogle Scholar
  190. 190.
    MacMillan SV, Ishiyama N, White GF, Palaniyar N, Hallett FR, Harauz G (2000) Myelin basic protein component C1 in increasing concentrations can elicit fusion, aggregation, and fragmentation of myelin-like membranes. Eur J Cell Biol 79:327–335Google Scholar
  191. 191.
    Boggs JM, Rangaraj G, Koshy KM, Ackerley C, Wood DD, Moscarello MA (1999) Highly deiminated isoform of myelin basic protein from multiple sclerosis brain causes fragmentation of lipid vesicles. J Neurosci Res 57:529–535PubMedGoogle Scholar
  192. 192.
    McLaurin J, Ackerley CA, Moscarello MA (1993) Localization of basic proteins in human myelin. J Neurosci Res 35:618–628PubMedGoogle Scholar
  193. 193.
    Beniac DR, Wood DD, Palaniyar N, Ottensmeyer FP, Moscarello MA, Harauz G (2000) Cryoelectron microscopy of protein-lipid complexes of human myelin basic protein charge isomers differing in degree of citrullination. J Struct Biol 129:80–95PubMedGoogle Scholar
  194. 194.
    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 302:476–483PubMedGoogle Scholar
  195. 195.
    Libich DS, Hill CMD, Haines JD, Harauz G (2003) Myelin basic protein has multiple calmodulin-binding sites. Biochem Biophys Res Commun 308:313–319PubMedGoogle Scholar
  196. 196.
    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 44:3524–3534PubMedGoogle Scholar
  197. 197.
    Hill CMD, Libich DS, Harauz G (2005) Assembly of tubulin by classic myelin basic protein isoforms and regulation by post-translational modification. Biochemistry 44:16672–16683PubMedGoogle Scholar
  198. 198.
    Shanshiashvili LV, Suknidze NC, Machaidze GG, Mikeladze DG, Ramsden JJ (2003) Adhesion and clustering of charge isomers of myelin basic protein at model myelin membranes. Arch Biochem Biophys 419:170–177PubMedGoogle Scholar
  199. 199.
    DeBruin LS, Haines JD, Wellhauser LA, Radeva G, Schonmann V, Bienzle D, Harauz G (2005) Developmental partitioning of myelin basic protein into membrane microdomains. J Neurosci Res 80:211–225PubMedGoogle Scholar
  200. 200.
    DeBruin LS, Harauz G (2006) White matter rafting – membrane microdomains in myelin. Neurochem Res (This issue)Google Scholar
  201. 201.
    Polverini E, Fasano A, Zito F, Riccio P, Cavatorta P (1999) Conformation of bovine myelin basic protein purified with bound lipids. Eur Biophys J 28:351–355PubMedGoogle Scholar
  202. 202.
    Farès C, Libich DS, Harauz G (2006) Solution NMR structure of an immunodominant epitope of myelin basic protein. FEBS J 273:601–614PubMedGoogle Scholar
  203. 203.
    Cuzner ML, Davison AN (1973) Changes in cerebral lysosomal enzyme activity and lipids in multiple sclerosis. J Neurol Sci 19:29–36PubMedGoogle Scholar
  204. 204.
    Cavatorta P, Giovanelli S, Bobba A, Riccio P, Quagliariello E (1991) Interaction of cations with lipid-free myelin basic protein. A spectroscopy study. Acta Neurol (Napoli) 13:162–169Google Scholar
  205. 205.
    Berlet HH, Bischoff H, Weinhardt F (1994) Divalent metals of myelin and their differential binding by myelin basic protein of bovine central nervous system. Neurosci Lett 179:75–78PubMedGoogle Scholar
  206. 206.
    Earl C, Chantry A, Mohammad N, Glynn P (1988) Zinc ions stabilise the association of basic protein with brain myelin membranes. J Neurochem 51:718–724PubMedGoogle Scholar
  207. 207.
    Cavatorta P, Giovanelli S, Bobba A, Riccio P, Szabo AG, Quagliariello E (1994) Myelin basic protein interaction with zinc and phosphate: fluorescence studies on the water-soluble form of the protein. Biophys J 66:1174–1179PubMedGoogle Scholar
  208. 208.
    Riccio P, Giovannelli S, Bobba A, Romito E, Fasano A, Bleve-Zacheo T, Favilla R, Quagliariello E, Cavatorta P (1995) Specificity of zinc binding to myelin basic protein. Neurochem Res 20:1107–1113PubMedGoogle Scholar
  209. 209.
    Tsang D, Tsang YS, Ho WK, Wong RN (1997) Myelin basic protein is a zinc-binding protein in brain: possible role in myelin compaction. Neurochem Res 22:811–819PubMedGoogle Scholar
  210. 210.
    Ho SY, Catalanotto FA, Lisak RP, Dore-Duffy P (1986) Zinc in multiple sclerosis. II: correlation with disease activity and elevated plasma membrane-bound zinc in erythrocytes from patients with multiple sclerosis. Ann Neurol 20:712–715PubMedGoogle Scholar
  211. 211.
    Berlet HH, Ilzenhofer H, Gass P (1991) Restricted endogenous proteolysis of myelin basic protein of zinc-treated myelin. Acta Neurol (Napoli) 13:145–152Google Scholar
  212. 212.
    Nuzzo S, Meneghini C, Mobilioo S, Haas H, Riccio P, Fasano A, Cavatorta P, Morante S (2002) An x-ray absorption spectroscopy study of the zinc environment in Langmuir-Blodgett phospholipid multilayers. Biophys J 83:3507–3512PubMedCrossRefGoogle Scholar
  213. 213.
    McLaurin J, Moscarello MA (1990) The preparation of antibodies reactive against citrulline-containing charge isomers of myelin basic protein but not against the arginine-containing charge isomers. Anal Biochem 191:272–277PubMedGoogle Scholar
  214. 214.
    McLaurin J, Hashim G, Moscarello MA (1992) An antibody specific for component 8 of myelin basic protein from normal brain reacts strongly with component 8 from multiple sclerosis brain. J Neurochem 59:1414–1420PubMedGoogle Scholar
  215. 215.
    Cruz TF, Moscarello MA (1985) Characterization of myelin fractions from human brain white matter. J Neurochem 44:1411–1418PubMedGoogle Scholar
  216. 216.
    Husted C (2006) Structural insight into the role of myelin basic protein in multiple sclerosis. Proc Natl Acad Sci USA 103:4339–4340PubMedGoogle Scholar
  217. 217.
    Matsuo A, Lee GC, Terai K, Takami K, Hickey WF, McGeer EG, McGeer PL (1997) Unmasking of an unusual myelin basic protein epitope during the process of myelin degeneration in humans: a potential mechanism for the generation of autoantigens. Am J Pathol 150:1253–1266PubMedGoogle Scholar
  218. 218.
    Liuzzi GM, Tamborra R, Ventola A, Bisaccia F, Quagliariello E, Riccio P (1996) Different recognition by clostripain of myelin basic protein in the lipid-free and lipid-bound forms. Biochem Biophys Res Commun 226:566–571PubMedGoogle Scholar
  219. 219.
    Medveczky P, Antal J, Patthy A, Kekesi K, Juhasz G, Szilagyi L, Graf L (2006) Myelin basic protein, an autoantigen in multiple sclerosis, is selectively processed by human trypsin 4. FEBS Lett 580:545–552PubMedGoogle Scholar
  220. 220.
    Napolitano L, Lebaron F, Scaletti J (1967) Preservation of myelin lamellar structure in the absence of lipid. A correlated chemical and morphological study. J Cell Biol 34:817–826PubMedGoogle Scholar
  221. 221.
    Tompkins TA, Moscarello MA (1994) The mechanism of stimulation of brain phospholipase C-alpha by myelin basic protein involves specific interactions. Biochim Biophys Acta 1206:208–214PubMedGoogle Scholar
  222. 222.
    Hill CMD, Harauz G (2005) Charge effects modulate actin assembly by classic myelin basic protein isoforms. Biochem Biophys Res Commun 329:362–369PubMedGoogle Scholar
  223. 223.
    Jantz D, Berg JM (2003) Expanding the DNA-recognition repertoire for zinc finger proteins beyond 20 amino acids. J Am Chem Soc 125:4960–4961PubMedGoogle Scholar
  224. 224.
    Martin BL, Luo S, Kintanar A, Chen M, Graves DJ (1998) Effect of citrulline for arginine replacement on the structure and turnover of phosphopeptide substrates of protein phosphatase-1. Arch Biochem Biophys 359:179–191PubMedGoogle Scholar
  225. 225.
    Imparl JM, Senshu T, Graves DJ (1995) Studies of calcineurin-calmodulin interaction: probing the role of arginine residues using peptidylarginine deiminase. Arch Biochem Biophys 318:370–377PubMedGoogle Scholar
  226. 226.
    Luo S, Martin BL, Senshu T, Graves DJ (1995) Enzymatic deimination of glycogen phosphorylase and a peptide of the phosphorylation site: identification of modification and roles in phosphorylation and activity. Arch Biochem Biophys 318:362–369PubMedGoogle Scholar
  227. 227.
    Eronina TB, Livanova NB, Chebotareva NA, Kurganov BI, Luo S, Graves DJ (1996) Deimination of glycogen phosphorylase b by peptidylarginine deiminase. Influence on the kinetical characteristics and dimer-tetramer transition. Biochimie 78:253–258PubMedGoogle Scholar
  228. 228.
    Bartleson C, Luo S, Graves DJ, Martin BL (2000) Arginine to citrulline replacement in substrates of phosphorylase kinase. Biochim Biophys Acta 1480:23–28PubMedGoogle Scholar
  229. 229.
    Edwards AM, Ross NW, Ulmer JB, Braun PE (1989) Interaction of myelin basic protein and proteolipid protein. J Neurosci Res 22:97–102PubMedGoogle Scholar
  230. 230.
    Tompkins TA, Moscarello MA (1991) A 57-kDa phosphatidylinositol-specific phospholipase C from bovine brain. J Biol Chem 266:4228–4236PubMedGoogle Scholar
  231. 231.
    Boggs JM, Rangaraj G (2000) Interaction of lipid-bound myelin basic protein with actin filaments and calmodulin. Biochemistry 39:7799–7806PubMedGoogle Scholar
  232. 232.
    Boggs JM, Rangaraj G, Gao W, Heng YM (2006) Effect of phosphorylation of myelin basic protein by MAPK on its interactions with actin and actin binding to a lipid membrane in vitro. Biochemistry 45:391–401PubMedGoogle Scholar
  233. 233.
    Dyer CA, Benjamins JA (1989) Organization of oligodendroglial membrane sheets: II. Galactocerebroside:antibody interactions signal changes in cytoskeleton and myelin basic protein. J Neurosci Res 24:212–221PubMedGoogle Scholar
  234. 234.
    Galiano MR, Andrieux A, Deloulme JC, Bosc C, Schweitzer A, Job D, Hallak ME (2006) Myelin basic protein functions as a microtubule stabilizing protein in differentiated oligodendrocytes. J Neurosci Res 84(In press)Google Scholar
  235. 235.
    Kies MW, Thompson EB, Alvord EC Jr (1965) The relationship of myelin proteins to experimental allergic encephalomyelitis. Ann N Y Acad Sci 122:148–160PubMedCrossRefGoogle Scholar
  236. 236.
    Whitaker JN (1998) Myelin basic protein in cerebrospinal fluid and other body fluids. Mult Scler 4:16–21PubMedGoogle Scholar
  237. 237.
    Panitch HS, Hooper CJ, Johnson KP (1980) CSF antibody to myelin basic protein. Measurement in patients with multiple sclerosis and subacute sclerosing panencephalitis. Arch Neurol 37:206–209PubMedGoogle Scholar
  238. 238.
    Warren KG, Catz I, McPherson TA (1983) CSF myelin basic protein levels in acute optic neuritis and multiple sclerosis. Can J Neurol Sci 10:235–238PubMedGoogle Scholar
  239. 239.
    Warren KG, Catz I (1987) A correlation between cerebrospinal fluid myelin basic protein and anti-myelin basic protein in multiple sclerosis patients. Ann Neurol 21:183–189PubMedGoogle Scholar
  240. 240.
    Warren KG, Catz I (1993) Autoantibodies to myelin basic protein within multiple sclerosis central nervous system tissue. J Neurol Sci 115:169–176PubMedGoogle Scholar
  241. 241.
    Warren KG, Catz I, Johnson E, Mielke B (1994) Anti-myelin basic protein and anti-proteolipid protein specific forms of multiple sclerosis. Ann Neurol 35:280–289PubMedGoogle Scholar
  242. 242.
    Warren KG, Catz I (1999) An extensive search for autoantibodies to myelin basic protein in cerebrospinal fluid of non-multiple-sclerosis patients: implications for the pathogenesis of multiple sclerosis. Eur Neurol 42:95–104PubMedGoogle Scholar
  243. 243.
    Warren KG, Catz I (2000) Kinetic profiles of cerebrospinal fluid anti-MBP in response to intravenous MBP synthetic peptide DENP(85)VVHFFKNIVTP(96)RT in multiple sclerosis patients. Mult Scler 6:300–311PubMedGoogle Scholar
  244. 244.
    Mouzaki A, Tselios T, Papathanassopoulos P, Matsoukas I, Chatzantoni K (2004) Immunotherapy for multiple sclerosis: basic insights for new clinical strategies. Curr Neurovasc Res 1:325–340PubMedGoogle Scholar
  245. 245.
    Tzakos AG, Troganis A, Theodorou V, Tselios T, Svarnas C, Matsoukas J, Apostolopoulos V, Gerothanassis IP (2005) Structure and function of the myelin proteins: current status and perspectives in relation to multiple sclerosis. Curr Med Chem 12:1569–1587PubMedGoogle Scholar
  246. 246.
    Mantzourani ED, Mavromoustakos TM, Platts JA, Matsoukas JM, Tselios TV (2005) Structural requirements for binding of myelin basic protein (MBP) peptides to MHC II: effects on immune regulation. Curr Med Chem 12:1521–1535PubMedGoogle Scholar
  247. 247.
    Nicholas AP, Whitaker JN (2002) Preparation of a monoclonal antibody to citrullinated epitopes: its characterization and some applications to immunohistochemistry in human brain. Glia 37:328–336PubMedGoogle Scholar
  248. 248.
    Nicholas AP, King JL, Sambandam T, Echols JD, Gupta KB, McInnis C, Whitaker JN (2003) Immunohistochemical localization of citrullinated proteins in adult rat brain. J Comp Neurol 459:251–266PubMedGoogle Scholar
  249. 249.
    Senshu T, Akiyama K, Ishigami A, Nomura K (1999) Studies on specificity of peptidylarginine deiminase reactions using an immunochemical probe that recognizes an enzymatically deiminated partial sequence of mouse keratin K1. J Dermatol Sci 21:113–126PubMedGoogle Scholar
  250. 250.
    Schlagel LJ, Bors L, Mitchell GW, King JL, Cao L, Kirk M, Whitaker JN (1997) Immunological effects of an arginine side chain contaminating synthetically prepared peptides. Mol Immunol 34:185–194PubMedGoogle Scholar
  251. 251.
    Zhou SR, Moscarello MA, Whitaker JN (1995) The effects of citrullination or variable amino-terminus acylation on the encephalitogenicity of human myelin basic protein in the PL/J mouse. J Neuroimmunol 62:147–152PubMedGoogle Scholar
  252. 252.
    Whitaker JN, Kirk KA, Herman PK, Zhou SR, Goodin RR, Moscarello MA, Wood DD (1992) An immunochemical comparison of human myelin basic protein and its modified, citrullinated form, C8. J Neuroimmunol 36:135–146PubMedGoogle Scholar
  253. 253.
    Zhou SR, Whitaker JN, Wood DD, Moscarello MA (1993) Immunological analysis of the amino terminal and the C8 isomer of human myelin basic protein. J Neuroimmunol 46:91–96PubMedGoogle Scholar
  254. 254.
    Cao L, Sun D, Whitaker JN (1998) Citrullinated myelin basic protein induces experimental autoimmune encephalomyelitis in Lewis rats through a diverse T cell repertoire. J Neuroimmunol 88:21–29PubMedGoogle Scholar
  255. 255.
    de Seze J, Dubucquoi S, Lefranc D, Virecoulon F, Nuez I, Dutoit V, Vermersch P, Prin L (2001) IgG reactivity against citrullinated myelin basic protein in multiple sclerosis. J Neuroimmunol 117:149–155PubMedGoogle Scholar
  256. 256.
    Rajendran L, Simons K (2005) Lipid rafts and membrane dynamics. J Cell Sci 118:1099–1102PubMedGoogle Scholar
  257. 257.
    Luger K, Mader AW, Richmond RK, Sargent DF, Richmond TJ (1997) Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature 389:251–260PubMedGoogle Scholar
  258. 258.
    Hansen JC, Lu X, Ross ED, Woody RW (2006) Intrinsic protein disorder, amino acid composition, and histone terminal domains. J Biol Chem 281:1853–1856PubMedGoogle Scholar
  259. 259.
    Pokholok DK, Harbison CT, Levine S, Cole M, Hannett NM, Lee TI, Bell GW, Walker K, Rolfe PA, Herbolsheimer E, Zeitlinger J, Lewitter F, Gifford DK, Young RA (2005) Genome-wide map of nucleosome acetylation and methylation in yeast. Cell 122:517–527PubMedGoogle Scholar
  260. 260.
    Thomas CE, Kelleher NL, Mizzen CA (2006) Mass spectrometric characterization of human histone H3: a bird’s eye view. J Proteome Res 5:240–247PubMedGoogle Scholar
  261. 261.
    Margueron R, Trojer P, Reinberg D (2005) The key to development: interpreting the histone code? Curr Opin Genet Dev 15:163–176PubMedGoogle Scholar
  262. 262.
    Trojer P, Reinberg D (2006) Histone lysine demethylases and their impact on epigenetics. Cell 125:213–217PubMedGoogle Scholar
  263. 263.
    Nakashima K, Hagiwara T, Yamada M (2002) Nuclear localization of peptidylarginine deiminase V and histone deimination in granulocytes. J Biol Chem 277:49562–49568PubMedGoogle Scholar
  264. 264.
    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 290:979–983PubMedGoogle Scholar
  265. 265.
    Wright PW, Bolling LC, Calvert ME, Sarmento OF, Berkeley EV, Shea MC, Hao Z, Jayes FC, Bush LA, Shetty J, Shore AN, Reddi PP, Tung KS, Samy E, Allietta MM, Sherman NE, Herr JC, Coonrod SA (2003) ePAD, an oocyte and early embryo-abundant peptidylarginine deiminase-like protein that localizes to egg cytoplasmic sheets. Dev Biol 256:73–88PubMedGoogle Scholar
  266. 266.
    Sarmento OF, Digilio LC, Wang Y, Perlin J, Herr JC, Allis CD, Coonrod SA (2004) Dynamic alterations of specific histone modifications during early murine development. J Cell Sci 117:4449–4459PubMedGoogle Scholar
  267. 267.
    Hagiwara T, Hidaka Y, Yamada M (2005) Deimination of histone H2A and H4 at arginine 3 in HL-60 granulocytes. Biochemistry 44:5827–5834PubMedGoogle Scholar
  268. 268.
    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 118:545–553PubMedGoogle Scholar
  269. 269.
    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 306:279–283PubMedGoogle Scholar
  270. 270.
    Hidaka Y, Hagiwara T, Yamada M (2005) Methylation of the guanidino group of arginine residues prevents citrullination by peptidylarginine deiminase IV. FEBS Lett 579:4088–4092PubMedGoogle Scholar
  271. 271.
    Denman RB (2005) PAD: the smoking gun behind arginine methylation signaling? Bioessays 27:242–246PubMedGoogle Scholar
  272. 272.
    Wysocka J, Allis CD, Coonrod S (2006) Histone arginine methylation and its dynamic regulation. Front Biosci 11:344–355PubMedGoogle Scholar
  273. 273.
    Bannister AJ, Schneider R, Kouzarides T (2002) Histone methylation: dynamic or static? Cell 109:801–806PubMedGoogle Scholar
  274. 274.
    Fackelmayer FO (2005) Protein arginine methyltransferases: guardians of the Arg? Trends Biochem Sci 30:666–671PubMedGoogle Scholar
  275. 275.
    Harauz G, Ishiyama N, Bates IR (2000) Analogous structural motifs in myelin basic protein and in MARCKS. Mol Cell Biochem 209:155–163PubMedGoogle Scholar
  276. 276.
    Soliven B (2001) Calcium signalling in cells of oligodendroglial lineage. Microsc Res Tech 52:672–679PubMedGoogle Scholar
  277. 277.
    Micu I, Jiang Q, Coderre E, Ridsdale A, Zhang L, Woulfe J, Yin X, Trapp BD, McRory JE, Rehak R, Zamponi GW, Wang W, Stys PK (2006) NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature 439:988–992PubMedGoogle Scholar
  278. 278.
    Sherman DL, Brophy PJ (2005) Mechanisms of axon ensheathment and myelin growth. Nat Rev Neurosci 6:683–690PubMedGoogle Scholar
  279. 279.
    Pritzker LB, Moscarello MA (1998) A novel microtubule independent effect of paclitaxel: the inhibition of peptidylarginine deiminase from bovine brain. Biochim Biophys Acta 1388:154–160PubMedGoogle Scholar
  280. 280.
    Cao L, Sun D, Cruz T, Moscarello MA, Ludwin SK, Whitaker JN (2000) Inhibition of experimental allergic encephalomyelitis in the Lewis rat by paclitaxel. J Neuroimmunol 108:103–111PubMedGoogle Scholar
  281. 281.
    Moscarello MA, Mak B, Nguyen TA, Wood DD, Mastronardi F, Ludwin SK (2002) Paclitaxel (Taxol) attenuates clinical disease in a spontaneously demyelinating transgenic mouse and induces remyelination. Mult Scler 8:130–138PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  1. 1.Department of Molecular and Cellular Biology, and Biophysics Interdepartmental GroupUniversity of GuelphGuelphCanada

Personalised recommendations