Is structural flexibility of antigen-binding loops involved in the affinity maturation of anti-DNA antibodies?
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.
Miyazaki
S
S
Life Science Research Information Division, Institute of Physical and Chemical Research (Riken), Saitama, Japan.
Shimura
J
J
Hirose
S
S
Sanokawa
R
R
Tsurui
H
H
Wakiya
M
M
Sugawara
H
H
Shirai
T
T
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
D000974:Antibodies, Antinuclear; D007135:Immunoglobulin Variable Region; D004247:DNA