title: Is structural flexibility of antigen-binding loops involved in the affinity maturation of anti-DNA antibodies?
abstract: Effects of somatic mutations in Ig variable region genes on the affinity maturation of autoantibodies were investigated using single precursor B cell-derived anti-double-stranded DNA mAb generated from an autoimmune disease-prone (NZB x NZW)F1 mouse. Analyses of DNA sequences, homology modeling on a graphic computer and molecular dynamics simulation of antigen-binding sites showed that any single site of mutation and changes in the electrostatic or hydrogen-bonding potential of the residues and in the three-dimensional structure could not solely explain the difference in DNA-binding activities. However, a significant increase in the flexibility of antigen-binding Fv loops, particularly VL CDR1 and VH CDR3, was associated with affinity-maturated anti-DNA antibodies. Such high flexibility of the FV loops may provide the environment where the antibodies could effectively interact with antigen DNA, a model consistent with the 'induced-fit' hypothesis of antigen-antibody interactions.
authors.affiliation: Life Science Research Information Division, Institute of Physical and Chemical Research (Riken), Saitama, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Miyazaki
authors.forename: J
authors.initials: J
authors.lastname: Shimura
authors.forename: S
authors.initials: S
authors.lastname: Hirose
authors.forename: R
authors.initials: R
authors.lastname: Sanokawa
authors.forename: H
authors.initials: H
authors.lastname: Tsurui
authors.forename: M
authors.initials: M
authors.lastname: Wakiya
authors.forename: H
authors.initials: H
authors.lastname: Sugawara
authors.forename: T
authors.initials: T
authors.lastname: Shirai
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000737:chemistry*; D000915:Antibody Affinity; D001483:Base Sequence; D004247:DNA / Q000276:immunology*; D005260:Female; D005803:Genes, Immunoglobulin; D006825:Hybridomas / Q000737:chemistry; D007135:Immunoglobulin Variable Region / Q000737:chemistry; D051379:Mice; D008814:Mice, Inbred NZB; D008863:Microspheres; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018583:Pliability; D011487:Protein Conformation
chemical_list: D000974:Antibodies, Antinuclear; D007135:Immunoglobulin Variable Region; D004247:DNA