A conformational study of the human and rat encephalitogenic myelin oligodendrocyte glycoprotein peptides 35-55.
Myelin oligodendrocyte glycoprotein (MOG), is considered an important central-nervous system-specific target autoantigen for primary demyelination in autoimmune diseases like multiple sclerosis. We have recently demonstrated that MOG or its derived peptide, MOG-(35-55)-peptide, are able to produce in animals, clinicopathologic signs that mimic multiple sclerosis. The rat MOG sequence spanning amino acids 35-55 [rMOG-(35-55)-peptide] differs from the human sequence [hMOG-(35-55)-peptide] by a single amino acid substitution, i.e. Pro42-->Ser. Mice injected with rMOG-(35-55)-peptide showed severe inflammation and demyelination throughout the central nervous system but, interestingly, mice injected with hMOG-(35 -55)-peptide showed only a few foci of mild inflammation with no demyelination. Circular dichroism and nuclear magnetic resonance spectroscopy have been used to structurally characterise the bioactive peptides hMOG-(35-55)-peptide and rMOG-(35-55)-peptide. In 0.1 M K2HPO4/KOH, 90% H2O/D2O solutions, these derived peptides have been shown, by NMR spectroscopy, to adopt detectable levels of short-range structure in equilibrium with unfolded conformers. On addition of 2,2,2-trifluoro-(2H3)ethanol, rMOG-(35-55)-peptide and hMOG-(35-55)-peptide adopt folded structures which have nuclear Overhauser enhancements characteristic of a poorly defined alpha-helix over residues 44-51. There are some indications of secondary structure also evident in the N-terminal region of rMOG-(35-55)-peptide. CD spectroscopy has revealed that in aqueous solution both peptides are unfolded but in 2.2.2-trifluoroethanol and, at micellar concentrations of sodium dodecyl sulfate, rMOG-(35-55)-peptide and, to a lesser extent, hMOG-(35-55)-peptide adopt helical conformations. In contrast, at non-micellar concentrations of SDS rMOG-(35-55)-peptide and hMOG-(35-55)-peptide adopt, according to CD spectroscopy, a beta-structure indicating that the peptides change conformation depending on the microenvironment of the amino acids.
Albouz-Abo
S
S
Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, Parkville, Australia.
Wilson
J C
JC
Bernard
C C
CC
von Itzstein
M
M
D000595:Amino Acid Sequence; D000818:Animals; D000954:Antigens, Surface / Q000737:chemistry; D002942:Circular Dichroism; D004660:Encephalitis / Q000139:chemically induced*; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000737:chemistry* / Q000494:pharmacology*; D063308:Myelin-Oligodendrocyte Glycoprotein; D009836:Oligodendroglia; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D051381:Rats; D012967:Sodium Dodecyl Sulfate
D000954:Antigens, Surface; C571326:MOG protein, human; C571327:Mog protein, mouse; C571328:Mog protein, rat; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D012967:Sodium Dodecyl Sulfate