Abstract
The low affinity receptor for IgG, Fc gamma RII (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. Fc gamma RII is a member of the immunoglobulin superfamily, containing an extracellular region of two Ig-like domains. The IgG binding site of human Fc gamma RII has been localized to an 8-amino acid segment of the second extracellular domain, Asn154-Ser161. 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 Fc gamma RII. Chimeric receptors generated by exchanging the extracellular domains and segments of domain 2 between Fc gamma RII and the structurally related Fc epsilon RI alpha chain were used to demonstrate that substitution of domain 1 in its entirety or the domain 2 regions encompassing residues Ser109-Val116 and Ser130-Thr135 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 Ser109-Val116 and Ser130-Thr135 domain 2 segments indicated that substitution of Lys113, Pro114, Leu115, Val116, Phe129, and His131 profoundly decreased the binding of hIgG1, whereas substitution of Asp133 and Pro134 increased binding. These findings suggest that not only is domain 1 contributing to the affinity of IgG binding by Fc gamma RII but, importantly, that the domain 2 regions Ser109-Val116 and Phe129-Thr135 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 Fc gamma RII 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.
Highlights
Cell surface receptors for the Fc portion of IgG (Fc␥R) are expressed on most hematopoietic cells, and through the binding of IgG they play a key role in homeostasis of the immune system and host protection against infection
Chimeric Receptors Identify Multiple Regions of Fc␥RII Involved in IgG Binding—In order to determine the roles of domain 1 and the B/C or CЈ/E loop regions of domain 2 in the binding of IgG by Fc␥RII, chimeric receptors were generated whereby each of these regions in Fc␥RII were replaced with the equivalent regions of the Fc⑀RI ␣ chain
The studies described provide evidence to suggest that the interaction of IgG with human Fc␥RII involves multiple regions juxtaposed in the receptor
Summary
Cell surface receptors for the Fc portion of IgG (Fc␥R) are expressed on most hematopoietic cells, and through the binding of IgG they play a key role in homeostasis of the immune system and host protection against infection. Chimeric Fc␥RII/Fc⑀RI ␣ chain receptors were used to demonstrate that the second extracellular domain of Fc␥RII was responsible for the binding of IgG, with a single direct binding region located between residues Asn154 and Ser161. The studies using chimeric Fc␥RII/Fc⑀RI receptors have identified three regions in the structurally homologous receptor, Fc⑀RI, capable of directly binding IgE: residues 87–128, 130 –135, and 154 –161, which encompass the B/C, CЈ/E, and F/G loops respectively [1, 18, 19]. Taken together, these findings suggest that the B/C
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