title: Structural and molecular analysis of a protective epitope of Lyme disease antigen OspA and antibody interactions.
abstract: The murine monoclonal antibody LA-2 recognizes a clinically protective epitope on outer surface protein (OspA) of Borrelia burgdorferi, the causative agent of Lyme disease in North America. Human antibody equivalence to LA-2 is the best serologic correlate of protective antibody responses following OspA vaccination. Understanding the structural and functional basis of the LA-2 protective epitope is important for developing OspA-based vaccines and discovering prophylactic antibodies against Lyme disease. Here, we present a detailed structure-based analysis of the LA-2/OspA interaction interface and identification of residues mediating antibody recognition. Mutations were introduced into both OspA and LA-2 on the basis of computational predictions on the crystal structure of the complex and experimentally tested for in vitro binding and borreliacidal activity. We find that Y32 and H49 on the LA-2 light chain, N52 on the LA-2 heavy chain and residues A208, N228 and N251 on OspA were the key constituents of OspA/LA-2 interface. These results reveal specific residues that may be exploited to modulate recognition of the protective epitope of OspA and have implications for developing prophylactic passive antibodies.
authors.affiliation: Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Boston, Massachusetts, USA.
authors.forename: Shivender
authors.initials: S
authors.lastname: Shandilya
authors.affiliation: Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Boston, Massachusetts, USA.
authors.forename: Nese
authors.initials: N
authors.lastname: Kurt Yilmaz
authors.affiliation: MassBiologics, University of Massachusetts Medical School, Boston, Massachusetts, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Sadowski
authors.affiliation: MassBiologics, University of Massachusetts Medical School, Boston, Massachusetts, USA.
authors.forename: Ejemel
authors.initials: E
authors.lastname: Monir
authors.affiliation: MassBiologics, University of Massachusetts Medical School, Boston, Massachusetts, USA.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Schiller
authors.affiliation: MassBiologics, University of Massachusetts Medical School, Boston, Massachusetts, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Thomas
authors.affiliation: MassBiologics, University of Massachusetts Medical School, Boston, Massachusetts, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Klempner
authors.affiliation: Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Boston, Massachusetts, USA.
authors.forename: Celia A
authors.initials: CA
authors.lastname: Schiffer
authors.affiliation: MassBiologics, University of Massachusetts Medical School, Boston, Massachusetts, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000954:Antigens, Surface / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001428:Bacterial Vaccines / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D025065:Borrelia burgdorferi / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000737:chemistry*; D006801:Humans; D008074:Lipoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008193:Lyme Disease / Q000276:immunology*; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D040681:Structural Homology, Protein
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000954:Antigens, Surface; D001425:Bacterial Outer Membrane Proteins; D001428:Bacterial Vaccines; D000939:Epitopes; D008074:Lipoproteins; C072045:OspA protein
keywords: Lyme disease; antibody; molecular interactions; mutations; protein structure; protein-protein; structural analysis; vaccine design