Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein

C. Breithaupt, A. Schubart, H. Zander, A. Skerra, R. Huber, Christopher Linington, U. Jacob

    Research output: Contribution to journalArticle

    96 Citations (Scopus)

    Abstract

    Multiple sclerosis is a chronic disease of the central nervous system (CNS) characterized by inflammation, demyelination, and axonal loss. The immunopathogenesis of demyelination in multiple sclerosis involves an autoantibody response to myelin oligodendrocyte glycoprotein (MOG), a type I transmembrane protein located at the surface of CNS myelin. Here we present the crystal structures of the extracellular domain of MOG (MOG(Igd)) at 1.45-Angstrom 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-Angstrom resolution. 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 with a surprisingly dominant contribution made by MOG residues 101-108 containing a strained loop that forms the upper edge of the putative ligand binding site. The sequence R(101)DHSYQEE(108) is unique for MOG, whereas large parts of the remaining sequence are conserved in potentially tolerogenic MOG homologues expressed outside the immuno-privileged environment of the CNS. Strikingly, the only sequence identical to DHSYQEE was found in a Chlamydia trachomatis protein of unknown function, raising the possibility that Chlamydia infections may play a role in the MOG-specific autoimmune response in man. Our data provide the structural basis for the development of diagnostic and therapeutic strategies targeting the pathogenic autoantibody response to MOG.

    Original languageEnglish
    Pages (from-to)9446-9451
    Number of pages5
    JournalPNAS
    Volume100
    Issue number16
    DOIs
    Publication statusPublished - Aug 2003

    Keywords

    • EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS
    • MULTIPLE-SCLEROSIS
    • CRYSTAL-STRUCTURE
    • T-CELL
    • MYELIN/OLIGODENDROCYTE GLYCOPROTEIN
    • MOLECULAR REPLACEMENT
    • MONOCLONAL-ANTIBODY
    • PROTEIN
    • SPECIFICITY
    • PROGRAM

    Cite this

    Breithaupt, C., Schubart, A., Zander, H., Skerra, A., Huber, R., Linington, C., & Jacob, U. (2003). Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein. PNAS, 100(16), 9446-9451. https://doi.org/10.1073/pnas.1133443100

    Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein. / Breithaupt, C.; Schubart, A.; Zander, H.; Skerra, A.; Huber, R.; Linington, Christopher; Jacob, U.

    In: PNAS, Vol. 100, No. 16, 08.2003, p. 9446-9451.

    Research output: Contribution to journalArticle

    Breithaupt, C, Schubart, A, Zander, H, Skerra, A, Huber, R, Linington, C & Jacob, U 2003, 'Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein', PNAS, vol. 100, no. 16, pp. 9446-9451. https://doi.org/10.1073/pnas.1133443100
    Breithaupt C, Schubart A, Zander H, Skerra A, Huber R, Linington C et al. Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein. PNAS. 2003 Aug;100(16):9446-9451. https://doi.org/10.1073/pnas.1133443100
    Breithaupt, C. ; Schubart, A. ; Zander, H. ; Skerra, A. ; Huber, R. ; Linington, Christopher ; Jacob, U. / Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein. In: PNAS. 2003 ; Vol. 100, No. 16. pp. 9446-9451.
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    abstract = "Multiple sclerosis is a chronic disease of the central nervous system (CNS) characterized by inflammation, demyelination, and axonal loss. The immunopathogenesis of demyelination in multiple sclerosis involves an autoantibody response to myelin oligodendrocyte glycoprotein (MOG), a type I transmembrane protein located at the surface of CNS myelin. Here we present the crystal structures of the extracellular domain of MOG (MOG(Igd)) at 1.45-Angstrom 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-Angstrom resolution. 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 with a surprisingly dominant contribution made by MOG residues 101-108 containing a strained loop that forms the upper edge of the putative ligand binding site. The sequence R(101)DHSYQEE(108) is unique for MOG, whereas large parts of the remaining sequence are conserved in potentially tolerogenic MOG homologues expressed outside the immuno-privileged environment of the CNS. Strikingly, the only sequence identical to DHSYQEE was found in a Chlamydia trachomatis protein of unknown function, raising the possibility that Chlamydia infections may play a role in the MOG-specific autoimmune response in man. Our data provide the structural basis for the development of diagnostic and therapeutic strategies targeting the pathogenic autoantibody response to MOG.",
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    AU - Breithaupt, C.

    AU - Schubart, A.

    AU - Zander, H.

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    AU - Huber, R.

    AU - Linington, Christopher

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    AB - Multiple sclerosis is a chronic disease of the central nervous system (CNS) characterized by inflammation, demyelination, and axonal loss. The immunopathogenesis of demyelination in multiple sclerosis involves an autoantibody response to myelin oligodendrocyte glycoprotein (MOG), a type I transmembrane protein located at the surface of CNS myelin. Here we present the crystal structures of the extracellular domain of MOG (MOG(Igd)) at 1.45-Angstrom 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-Angstrom resolution. 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 with a surprisingly dominant contribution made by MOG residues 101-108 containing a strained loop that forms the upper edge of the putative ligand binding site. The sequence R(101)DHSYQEE(108) is unique for MOG, whereas large parts of the remaining sequence are conserved in potentially tolerogenic MOG homologues expressed outside the immuno-privileged environment of the CNS. Strikingly, the only sequence identical to DHSYQEE was found in a Chlamydia trachomatis protein of unknown function, raising the possibility that Chlamydia infections may play a role in the MOG-specific autoimmune response in man. Our data provide the structural basis for the development of diagnostic and therapeutic strategies targeting the pathogenic autoantibody response to MOG.

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    KW - T-CELL

    KW - MYELIN/OLIGODENDROCYTE GLYCOPROTEIN

    KW - MOLECULAR REPLACEMENT

    KW - MONOCLONAL-ANTIBODY

    KW - PROTEIN

    KW - SPECIFICITY

    KW - PROGRAM

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    DO - 10.1073/pnas.1133443100

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    JO - PNAS

    JF - PNAS

    SN - 0027-8424

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    ER -