Crystal Structure of the HSV-1 Fc Receptor Bound to Fc Reveals a Mechanism for Antibody Bipolar Bridging

Herpes simplex virus type-1 expresses a heterodimeric Fc receptor, gE-gI, on the surfaces of virions and infected cells that binds the Fc region of host immunoglobulin G and is implicated in the cell-to-cell spread of virus. gE-gI binds immunoglobulin G at the basic pH of the cell surface and releases it at the acidic pH of lysosomes, consistent with a role in facilitating the degradation of antiviral antibodies. Here we identify the C-terminal domain of the gE ectodomain (CgE) as the minimal Fc-binding domain and present a 1.78-Å CgE structure. A 5-Å gE-gI/Fc crystal structure, which was independently verified by a theoretical prediction method, reveals that CgE binds Fc at the CH2-CH3 interface, the binding site for several mammalian and bacterial Fc-binding proteins. The structure identifies interface histidines that may confer pH-dependent binding and regions of CgE implicated in cell-to-cell spread of virus. The ternary organization of the gE-gI/Fc complex is compatible with antibody bipolar bridging, which can interfere with the antiviral immune response. ; © 2006 Sprague et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: January 9, 2006; Accepted: March 7, 2006; Published: May 2, 2006 We thank Inder Nangiana, Peter Snow, and Bjoern Phillips (California Institute of Technology Protein Expression Facility) for insect cell expression of gE-gI and CgE; Evelyn Cheung and Liz Leyton for assistance in crystallization; Leonard Thomas for assistance with derivative screening; and Andrew Herr, Malini Raghavan, Elaine Bearer, and Anthony West for critical reading of the manuscript. N-terminal sequencing and mass spectrometry were done by the Protein/Peptide Microanalytical Lab at the California Institute of Technology. Crystallographic data were collected at Stanford Synchrotron Radiation Laboratory beamlines 9–1 ...