The Crystal Structure of Myelin Oligodendrocyte Glycoprotein, a Key Autoantigen in Multiple Sclerosis
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 immunopatholog...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 100; no. 19; pp. 11059 - 11064 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
16.09.2003
National Acad Sciences |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 Abbreviations: DTSSP, 3,3′-dithiobis(sulfosuccinimidylpropionate); EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; MOGED, MOG extracellular domain; MS, multiple sclerosis; P0, myelin protein zero. Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.rcsb.org (PDB ID code 1PY9). C.S.C., H.H.R., and T.B. contributed equally to this work. This paper was submitted directly (Track II) to the PNAS office. Edited by David R. Davies, National Institutes of Health, Bethesda, MD, and approved July 21, 2003 To whom correspondence may be addressed. E-mail: jamie.rossjohn@med.monash.edu.au or c.bernard@latrobe.edu.au. |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.1833158100 |