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Mutagenesis Within Human FcRI Differentially Affects Human and Murine IgE Binding¹

Graham A. Mackay^2,*, Mark D. Hulett^3,, Justin P. D. Cook^*, Halina M. Trist, Alistair J. Henry^4,*, James M. McDonnell, Andrew J. Beavil^*, Rebecca L. Beavil^*, Brian J. Sutton^*, P. Mark Hogarth and Hannah J. Gould^5,*

^* Randall Centre, New Hunt’s House, King’s College London, Guy’s Campus, London, United Kingdom; Helen M. Schutt Laboratory for Immunology, Austin Research Institute, Austin Repatriation Medical Center, Heidelberg, Victoria, Australia; and Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, Oxford, United Kingdom

Soluble fragments of the -chain of FcRI, the high-affinity receptor for IgE, compete with membrane-bound receptors for IgE and may thus provide a means to combat allergic responses. Mutagenesis within FcRI is used in this study, in conjunction with the crystal structure of the FcRI/IgE complex, to define the relative importance of specific residues within human FcRI for IgE binding. We have also compared the effects of these mutants on binding to both human and mouse IgE, with a view to evaluating the mouse as an appropriate model for the analysis of future agents designed to mimic the human FcRI and attenuate allergic disease. Three residues within the C-C' region of the FcRI 2 domain and two residues within the 2 proximal loops of the 1 domain were selected for mutagenesis and tested in binding assays with human and mouse IgE. All three 2 mutations (K117D, W130A, and Y131A) reduced the affinity of human IgE binding to different extents, but K117D had a far more pronounced effect on mouse IgE binding, and although Y131A had little effect, W130A modestly enhanced binding to mouse IgE. The mutations in 1 (R15A and F17A) diminished binding to both human and mouse IgE, with these effects most likely caused by disruption of the 1/2 interface. Our results demonstrate that the effects of mutations in human FcRI on mouse IgE binding, and hence the inhibitory properties of human receptor-based peptides assayed in rodent models of allergy, may not necessarily reflect their activity in a human IgE-based system.

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