Structural mechanism for affinity maturation of an anti-lysozyme antibody.
In the immune response against a typical T cell-dependent protein antigen, the affinity maturation process is fast and is associated with the early class switch from IgM to IgG. As such, a comprehension of the molecular basis of affinity maturation could be of great importance in biomedical and biotechnological applications. Affinity maturation of anti-protein antibodies has been reported to be the result of small structural changes, mostly confined to the periphery of the antigen-combining site. However, little is understood about how these small structural changes account for the increase in the affinity toward the antigen. Herein, we present the three-dimensional structure of the Fab fragment from BALB/c mouse mAb F10.6.6 in complex with the antigen lysozyme. This antibody was obtained from a long-term exposure to the antigen. mAb F10.6.6, and the previously described antibody D44.1, are the result of identical or nearly identical somatic recombination events. However, different mutations in the framework and variable regions result in an approximately 10(3) higher affinity for the F10.6.6 antibody. The comparison of the three-dimensional structures of these Fab-lysozyme complexes reveals that the affinity maturation produces a fine tuning of the complementarity of the antigen-combining site toward the epitope, explaining at the molecular level how the immune system is able to increase the affinity of an anti-protein antibody to subnanomolar levels.
Instituto Leloir, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina and Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1405 Buenos Aires, Argentina.
Ana
A
Cauerhff
Fernando A
FA
Goldbaum
Bradford C
BC
Braden
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000915:Antibody Affinity; D000941:Antigens; D002645:Chickens; D022801:Complementarity Determining Regions; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D046911:Macromolecular Substances; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009113:Muramidase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000276:immunology*; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics
D000911:Antibodies, Monoclonal; D000941:Antigens; D022801:Complementarity Determining Regions; D007140:Immunoglobulin Fab Fragments; D046911:Macromolecular Substances; D009113:Muramidase