The Crystal Structure of Myelin Oligodendrocyte Glycoprotein, a Key Autoantigen in Multiple Sclerosis

• Published in: Proceedings of the National Academy of Sciences - PNAS 2003-09, Vol.100 (19), p.11059-11064
• Main Authors: Clements, Craig S., Reid, Hugh H., Beddoe, Travis, Tynan, Fleur E., Perugini, Matthew A., Johns, Terrance G., Claude C. A. Bernard, Rossjohn, Jamie
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Antigens; Autoantigens; Autoantigens - chemistry; Autoantigens - metabolism; Biological Sciences; Central nervous system; Crystallography, X-Ray; Demyelinating diseases; Dimers; Electrophoresis, Polyacrylamide Gel; Gels; Glycoproteins; homophilic adhesion receptor; Models, Molecular; Molecular Sequence Data; Molecules; Multiple sclerosis; Multiple Sclerosis - metabolism; Myelin; Myelin Proteins; Myelin sheath; Myelin-Associated Glycoprotein - chemistry; Myelin-Associated Glycoprotein - metabolism; Myelin-Oligodendrocyte Glycoprotein; Neurology; Receptors; Sequence Homology, Amino Acid; T lymphocytes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1833158100

Myelin oligodendrocyte glycoprotein (MOG) is a key CNS-specific autoantigen for primary demyelination in multiple sclerosis. Although the disease-inducing role of MOG has been established, its precise function in the CNS remains obscure. To gain new insights into the physiological and immunopathological role of MOG, we determined the 1.8-Å crystal structure of the MOG extracellular domain$(MOG_{ED}).\>MOG_{ED}$adopts a classical Ig (Ig variable domain) fold that was observed to form an antiparallel head-to-tail dimer. A dimeric form of native MOG was observed, and MOGEDwas also shown to dimerize in solution, consistent with the view of MOG acting as a homophilic adhesion receptor. The MOG35-55peptide, a major encephalitogenic determinant recognized by both T cells and demyelinating autoantibodies, is partly occluded within the dimer interface. The structure of this key autoantigen suggests a relationship between the dimeric form of MOG within the myelin sheath and a breakdown of immunological tolerance to MOG that is observed in multiple sclerosis.