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The Human Cytomegalovirus Fc Receptor gp68 Binds the Fc C_H2-C_H3 Interface of Immunoglobulin G

Elizabeth R. Sprague,¹ Henrike Reinhard,² Evelyn J. Cheung,¹ Alexander H. Farley,¹ Robin Deis Trujillo,^1, Hartmut Hengel,² and Pamela J. Bjorkman^1,3*

Division of Biology,¹ Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California 91125,³ Institut für Virologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany²

Received 5 July 2007/ Accepted 15 January 2008

Recognition of immunoglobulin G (IgG) by surface receptors for the Fc domain of immunoglobulin G (Fc), FcRs, can trigger both humoral and cellular immune responses. Two human cytomegalovirus (HCMV)-encoded type I transmembrane receptors with Fc-binding properties (vFcRs), gp34 and gp68, have been identified on the surface of HCMV-infected cells and are assumed to confer protection against IgG-mediated immunity. Here we show that Fc recognition by both vFcRs occurs independently of N-linked glycosylation of Fc, in contrast with the properties of host FcRs. To gain further insight into the interaction with Fc, truncation mutants of the vFcR gp68 ectodomain were probed for Fc binding, resulting in localization of the Fc binding site on gp68 to residues 71 to 289, a region including an immunoglobulin-like domain. Gel filtration and biosensor binding experiments revealed that, unlike host FcRs but similar to the herpes simplex virus type 1 (HSV-1) Fc receptor gE-gI, gp68 binds to the C_H2-C_H3 interdomain interface of the Fc dimer with a nanomolar affinity and a 2:1 stoichiometry. Unlike gE-gI, which binds Fc at the slightly basic pH of the extracellular milieu but not at the acidic pH of endosomes, the gp68/Fc complex is stable at pH values from 5.6 to pH 8.1. These data indicate that the mechanistic details of Fc binding by HCMV gp68 differ from those of host FcRs and from that of HSV-1 gE-gI, suggesting distinct functional and recognition properties.

Published ahead of print on 23 January 2008.

Present address: Department of Microbiology and Immunology, Stanford University, Palo Alto, CA 94305.