The crystal structure of myelin oligodendrocyte glycoprotein, a key autoantigen in multiple sclerosis
Craig S Clements1, Hugh H Reid, Travis Beddoe
1Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3168, Australia.
Abstract:
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-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. A dimeric form of native MOG was observed, and MOGED was also shown to dimerize in solution, 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. 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.
Insights
The crystal structure of myelin oligodendrocyte glycoprotein (MOG) reveals it forms dimers, potentially explaining its role in multiple sclerosis (MS) and immune tolerance breakdown.
Area of Science:
- Neuroimmunology
- Structural Biology
- Myelin Biology
Background:
- Myelin oligodendrocyte glycoprotein (MOG) is a key autoantigen in multiple sclerosis (MS), a demyelinating disease.
- The precise physiological and immunopathological functions of MOG in the central nervous system (CNS) remain unclear.
- Understanding MOG's structure is crucial for elucidating its role in demyelination and immune tolerance.
Purpose of the Study:
- To determine the crystal structure of the MOG extracellular domain (MOGED).
- To gain insights into the physiological and immunopathological roles of MOG.
- To explore the structural basis of MOG's involvement in multiple sclerosis.
Main Methods:
- X-ray crystallography was used to determine the 1.8-Å crystal structure of the MOG extracellular domain (MOGED).
- Analytical ultracentrifugation and other biophysical methods were employed to assess MOGED dimerization in solution.
- Structural analysis focused on identifying MOG's fold, oligomerization state, and the accessibility of key epitopes.
Main Results:
- MOGED adopts a classical immunoglobulin (Ig) variable domain fold.
- MOGED forms an antiparallel head-to-tail dimer, and native MOG also dimerizes in solution, suggesting MOG functions as a homophilic adhesion receptor.
- The encephalitogenic MOG35-55 peptide, a target in MS, is partially occluded within the MOG dimer interface.
Conclusions:
- The dimeric structure of MOG suggests a potential mechanism for its role as a homophilic adhesion molecule in the CNS.
- The occlusion of the MOG35-55 peptide within the dimer interface may influence T cell and autoantibody recognition.
- This structural insight provides a link between MOG's dimeric form in myelin and the breakdown of immunological tolerance observed in multiple sclerosis.
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