HUMAN FC-GAMMA-RI AND FC-GAMMA-RII INTERACT WITH DISTINCT BUT OVERLAPPING SITES ON HUMAN-IGG

Cellular receptors for IgG (Fc-gamma-R) mediate important protective functions. By using site-specific mutants of a chimeric antibody (mouse V H domain and L chain; human IgG3 C H domains), we have demonstrated that human Fc-gamma-RI interacts with a site in the lower hinge of human IgG (residues 234 to 237) and that this interaction dictates Fc-gamma-RI-mediated superoxide generation. Mutations at position 235 resulted in the most profound reductions in Fc-gamma-RI recognition. We have also mapped an interaction site for Fc-gamma-RII to the same region; however, mutations at position 234 and 237 resulted in the greatest reductions in Fc-gamma-RII recognition. The two receptors appear to recognize overlapping but nonidentical sites on the lower hinge of IgG. Deviations from the optimal motif 234-Leu-Leu-Gly-Gly-237 may then explain the human IgG subclass specificity profile for human Fc-gamma-RI and Fc-gamma-RII.