Abstract
Outer surface protein A (OspA) is a major lipoprotein of the Borrelia burgdorferi spirochete, the causative agent of Lyme disease. Vaccination with OspA generates an immune response that can prevent bacterial transmission to a mammalian host during the attachment of an infected tick. However, the protective capacity of immune sera cannot be predicted by measuring total anti-OspA antibody. The murine monoclonal antibody LA-2 defines an important protective B-cell epitope of OspA against which protective sera have strong levels of reactivity. We have now mapped the LA-2 epitope of OspA using both NMR chemical-shift perturbation measurements in solution and X-ray crystal structure determination. LA-2 recognizes the three surface-exposed loops of the C-terminal domain of OspA that are on the tip of the elongated molecule most distant from the lipid-modified N terminus. The structure suggests that the natural variation at OspA sequence position 208 in the first loop is a major limiting factor for antibody cross-reactivity between different Lyme disease-causing Borrelia strains. The unusual Fab-dominated lattice of the crystal also permits a rare view of antigen flexibility within an antigen:antibody complex. These results provide a rationale for improvements in OspA-based vaccines and suggest possible designs for more direct tests of antibody protective levels in vaccinated individuals.
Publication types
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Comparative Study
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Antigen-Antibody Complex / chemistry
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Antigen-Antibody Complex / immunology
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Antigens, Bacterial / chemistry
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Antigens, Bacterial / genetics
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Antigens, Bacterial / immunology
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Antigens, Surface / chemistry*
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Antigens, Surface / genetics
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Antigens, Surface / immunology*
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Bacterial Outer Membrane Proteins / chemistry*
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Bacterial Outer Membrane Proteins / genetics
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Bacterial Outer Membrane Proteins / immunology*
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Bacterial Vaccines
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Borrelia burgdorferi Group / chemistry
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Borrelia burgdorferi Group / genetics
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Borrelia burgdorferi Group / immunology*
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Crystallography, X-Ray
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Epitope Mapping
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Epitopes, B-Lymphocyte / chemistry*
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Epitopes, B-Lymphocyte / genetics
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Epitopes, B-Lymphocyte / immunology*
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Genetic Variation / genetics
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Immunoglobulin Fab Fragments / chemistry
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Immunoglobulin Fab Fragments / immunology
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Lipoproteins*
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Lyme Disease / immunology*
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Lyme Disease Vaccines / chemistry*
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Lyme Disease Vaccines / genetics
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Lyme Disease Vaccines / immunology*
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Models, Molecular
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Molecular Sequence Data
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Mutation
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Nuclear Magnetic Resonance, Biomolecular
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Sequence Alignment
Substances
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Antigen-Antibody Complex
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Antigens, Bacterial
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Antigens, Surface
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Bacterial Outer Membrane Proteins
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Bacterial Vaccines
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Epitopes, B-Lymphocyte
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Immunoglobulin Fab Fragments
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Lipoproteins
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Lyme Disease Vaccines
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OspA protein