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A conformational study of the human and rat encephalitogenic myelin oligodendrocyte glycoprotein peptides 35-55
S Albouz-Abo1, J C Wilson, C C Bernard
1Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, Parkville, Australia.
Abstract:
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.
Insights
Myelin oligodendrocyte glycoprotein (MOG) peptides can induce multiple sclerosis-like symptoms in animals. Structural differences in human MOG peptide explain its reduced disease-inducing capacity compared to rat MOG peptide.
Area of Science:
- Neuroimmunology
- Structural Biology
- Biochemistry
Background:
- Myelin oligodendrocyte glycoprotein (MOG) is a key autoantigen in demyelinating diseases like multiple sclerosis.
- MOG-derived peptides can experimentally induce autoimmune demyelination, mimicking disease pathology.
Purpose of the Study:
- To investigate the structural basis for the differential pathogenicity of rat MOG-(35-55) and human MOG-(35-55) peptides.
- To characterize the conformational properties of these peptides in various environments.
Main Methods:
- Animal models of experimental autoimmune encephalomyelitis (EAE) were used.
- Structural characterization of peptides was performed using Nuclear Magnetic Resonance (NMR) spectroscopy and Circular Dichroism (CD) spectroscopy.
Main Results:
- Rat MOG-(35-55) peptide induced severe CNS inflammation and demyelination in mice.
- Human MOG-(35-55) peptide, differing by one amino acid, caused only mild inflammation and no demyelination.
- Both peptides adopted alpha-helical structures in trifluoroethanol and micellar SDS, but beta-structures in non-micellar SDS, indicating environmental sensitivity.
Conclusions:
- A single amino acid difference significantly impacts the encephalitogenic potential of MOG peptides.
- The conformation of MOG peptides is influenced by their microenvironment, affecting their biological activity.