Structural basis of the interaction between IgG and Fc gamma receptors

The binding of multivalent antigen-antibody complexes to receptors for the Fc portion of IgG (Fc gamma R) induces the clustering of the Fc gamma R and triggers cell activation leading to defence reactions against pathogens. T he Fc portion of IgG consists of two identical polypeptide chains which are related to each other by a 2-fold axis and are folded in two structural do mains, the C(H)2 domain, near the flexible hinge region of the IgG molecule , and the C(H)3 domain. We studied the interaction in solution between the Fc fragment of mouse IgG2b and the extracellular region of mouse Fc gamma R II. We find that one Fc molecule binds one Fc gamma RII molecule only. Usin g NMR spectroscopy, we show that Fc gamma RII binds to a negatively charged area of the C(H)2 domain, corresponding to the lower hinge region, and tha t the binding of Fc gamma RII onto one of the two symmetrically related sit es on the Fc induces a conformational change in the other site. We therefor e propose a model that explains why IgG molecules are unable to trigger Fc gamma R-mediated cellular responses spontaneously in the absence of crossli nking by multivalent antigens. (C) 2000 Academic Press.