The low affinity receptor for IgG, FcRII (CD32), has a wide distribution on hematopoietic cells where it is responsible for a diverse range of cellular responses crucial for immune regulation and resistance to infection. FcRII is a member of the immunoglobulin superfamily, containing an extracellular region of two Ig-like domains. The IgG binding site of human FcRII has been localized to an 8-amino acid segment of the second extracellular domain, Asn-Ser. In this study, evidence is presented to suggest that domain 1 and two additional regions of domain 2 also contribute to the binding of IgG by FcRII. Chimeric receptors generated by exchanging the extracellular domains and segments of domain 2 between FcRII and the structurally related FcRI chain were used to demonstrate that substitution of domain 1 in its entirety or the domain 2 regions encompassing residues Ser-Val and Ser-Thr resulted in a loss of the ability of these receptors to bind hIgG1 in dimeric form. Site-directed mutagenesis performed on individual residues within and flanking the Ser-Val and Ser-Thr domain 2 segments indicated that substitution of Lys, Pro, Leu, Val, Phe, and His profoundly decreased the binding of hIgG1, whereas substitution of Asp and Pro increased binding. These findings suggest that not only is domain 1 contributing to the affinity of IgG binding by FcRII but, importantly, that the domain 2 regions Ser-Val and Phe-Thr also play key roles in the binding of hIgG1. The location of these binding regions on a molecular model of the entire extracellular region of FcRII indicates that they comprise loops that are juxtaposed in domain 2 at the interface with domain 1, with the putative crucial binding residues forming a hydrophobic pocket surrounded by a wall of predominantly aromatic and basic residues.

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