Monoclonal antibody to a DNA-binding domain of p53 mimics charge structure of DNA: anti-idiotypes to the anti-p53 antibody are anti-DNA.
Antibodies to DNA are important markers of various autoimmune diseases and can be pathogenic; however, their generation is not understood. We previously reported that anti-DNA antibodies could be induced in mice by idiotypic immunization to PAb-421, an antibody to a DNA-binding domain of p53. We now report that two monoclonal antibodies of moderate affinity (K(D) asymptotically equal to 10(-7)), raised from PAb-421-immunized mice, specifically recognized both PAb-421 and DNA. These antibodies feature multiple arginine residues in the antigen-binding site, a unique characteristic of disease-associated anti-DNA antibodies; nevertheless, these anti-DNA antibodies show specific complementarity to PAb-421 by competing with p53 for PAb-421 binding and recognize defined oligonucleotides with a specificity similar to that of p53. To study the structural basis for the cross-recognition of PAb-421 and DNA by the anti-DNA antibodies, we constructed computer models (fine-tuned by protein-protein docking) of PAb-421 and one of the monoclonal anti-DNA antibodies. The modeled structures manifested structural complementarity. Most notably, the modeled structure of PAb-421 resembled the structure of DNA by the positions of negatively charged groups and aromatic side chains. Thus, a protein molecule may mimic the structure of DNA and the elusive generation of anti-DNA antibodies could be explained by idiotypic immunity to a DNA-binding protein, like p53.
Herkel
Johannes
J
Department of Medicine, Johannes Gutenberg University, Mainz, Germany.
Kam
Na'aman
N
Erez
Neta
N
Mimran
Avishai
A
Heifetz
Alexander
A
Eisenstein
Miriam
M
Rotter
Varda
V
Cohen
Irun R
IR
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D004247:DNA / Q000276:immunology* / Q000378:metabolism; D007130:Immunoglobulin Idiotypes / Q000276:immunology*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000276:immunology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016159:Tumor Suppressor Protein p53 / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D007130:Immunoglobulin Idiotypes; D009841:Oligonucleotides; D016159:Tumor Suppressor Protein p53; D004247:DNA