Several structures for Myelin Oligodendrocyte Glycoprotein or MOG have been solved!
MOG or myelin oligodendrocyte glycoprotein is a key central nervous system (CNS)-specific autoantigen for primary demyelination in multiple sclerosis. The gene product of myelin oligodendrocyte glycoprotein or MOG is a membrane protein expressed on the oligodendrocyte cell surface and the outermost surface of myelin sheaths, in the brain and spinal cord. Due to this localization, it is a primary target antigen involved in immune-mediated demyelination. The myelin oligodendrocyte glycoprotein (MOG) is thought to be involved in completion and maintenance of the myelin sheath and in cell-cell communication. In addition, alternatively spliced transcript variants of MOG encoding different isoforms have been identified. MOG is a transmembrane protein that belongs to the immunoglobulin superfamily. The protein contains an Ig-like domain and has two potential membrane-spanning regions. Even thought the disease-inducing role of MOG has been established, its precise function in the CNS is still unknown.
Three possible functions for myelin oligodendrocyte glycoprotein or MOG have been suggested in the past:
(1) The protein may function as a cellular adhesive molecule.
(2) The protein may function as a regulator of oligodendrocyte microtubule stability.
(3) The protein may function as a mediator of interactions between myelin and the immune system, as well as the complement cascade.
Amor et al. in 1996 used myelin basic protein (MBP) and synthetic MBP peptides to screen for their ability to induce experimental allergic encephalomyelitis in Biozzi ABH (H-2Ag7) mice. Their data suggest the presence of a peptide core between MBP 21-26 (HARHGF). This peptide motif contains similar elements to the previously defined encephalitogenic MOG 1-22 and PLP 56-70 peptides. The authors further investigated the fine specificity of these epitopes using frame-shifted peptides, which indicated cores between MOG 9-15 (GYPIRAL) and PLP 62-68 (NVIHAFQ). Based on these pathogenic peptides, a putative H-2Ag7 binding motif was suggested that contains a series of hydrophobic, basic, small, and large hydrophobic residues within a 6 to 7 amino acid core. The authors suggest that these findings may have relevance in the design of strategies in the treatment of experimental autoimmune diseases in animals that express this haplotype.
Figure 1: Crystal structures of the extracellular domain of MOG (MOGIgd) at 1.45-A resolution and the complex of MOGIgd with the antigen-binding fragment (Fab) of the MOG-specific demyelinating monoclonal antibody 8-18C5 at 3.0-A resolution.
The demyelination in multiple sclerosis involves an autoantibody response to myelin oligodendrocyte glycoprotein. Breithaupt et al. in 2003 reported the crystal structures of the extracellular domain of MOG (MOGIgd) at 1.45-A resolution and the complex of MOG-Igd with the antigen-binding fragment (Fab) of the MOG-specific demyelinating monoclonal antibody 8-18C5 at 3.0-A resolution. The structures showed that MOG-Igd adopts an IgV like fold with the A'GFCC'C" sheet harboring a cavity similar to the one used by the costimulatory molecule B7-2 to bind its ligand CTLA4. The antibody 8-18C5 binds to three loops located at the membrane-distal side of MOG. Dominant contribution to these interactions are made by MOG residues 101-108 containing a strained loop that forms the upper edge of the putative ligand binding site. The sequence R101DHSYQEE108 is unique for MOG. However, large parts of the remaining sequence are conserved in MOG homologues that potentially produce immunological tolerance which are expressed outside the immuno-privileged environment of the CNS.
Figure 1: Crystal structure of myelin oligodendrocyte glycoprotein, a key autoantigen in multiple sclerosis.
To gain new insights into the physiological and immunopathological role of MOG, Clements et al. also in 2003 determined the 1.8-A crystal structure of the MOG extracellular domain (MOGED). MOGED adopts a classical Ig (Ig variable domain) fold that was observed to form an antiparallel head-to-tail dimer. The dimeric form of native MOG was also observed. MOGED was also shown to dimerize in solution. This observation is consistent with the view of MOG acting as a homophilic adhesion receptor. The MOG35-55 peptide, a major encephalitogenic determinant recognized by both T cells and demyelinating autoantibodies, is partly occluded within the dimer interface.
MOG peptides can be synthesized using automated solid phase peptide synthesis (SPPS) which are useful tools for the study of protein-protein or protein-peptide interactions to help elucidate the role of MOG and/or similar proteins.
Amor S, O'Neill JK, Morris MM, Smith RM, Wraith DC, Groome N, Travers PJ, Baker D,; Encephalitogenic epitopes of myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein for experimental allergic encephalomyelitis induction in Biozzi ABH (H-2Ag7) mice share an amino acid motif. J Immunol. 1996 Apr 15;156(8):3000-8.
Breithaupt C, Schubart A, Zander H, Skerra A, Huber R, Linington C, Jacob U; Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein. Proc.Natl.Acad.Sci.Usa (2003) 100 p.9446
Clements CS, Reid HH, Beddoe T, Tynan FE, Perugini MA, Johns TG, Bernard CC, Rossjohn J.; The crystal structure of myelin oligodendrocyte glycoprotein, a key autoantigen in multiple sclerosis. Proc.Natl.Acad.Sci.Usa (2003) 100 p.11059