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J Biol Chem, Vol. 274, Issue 19, 13345-13352, May 7, 1999

Fine Structure Analysis of Interaction of FcRI with IgE

Mark D. Hulett, Ross I. Brinkworth^¶, Ian F. C. McKenzie, and P. Mark Hogarth

From  The Austin Research Institute, Austin Hospital, Studley Road, Heidelberg, Victoria 3084, Australia and ^¶ The Centre for Drug Design and Development, University of Queensland, Brisbane, Queensland 4072, Australia

The high affinity receptor for IgE (FcRI) plays an integral role in triggering IgE-mediated hypersensitivity reactions. The IgE-interactive site of human FcRI has previously been broadly mapped to several large regions in the second extracellular domain (D2) of the -subunit (FcRI). In this study, the IgE binding site of human FcRI has been further localized to subregions of D2, and key residues putatively involved in the interaction with IgE have been identified. Chimeric receptors generated between FcRI and the functionally distinct but structurally homologous low affinity receptor for IgG (FcRIIa) have been used to localize two IgE binding regions of FcRI to amino acid segments Tyr¹²⁹-His¹³⁴ and Lys¹⁵⁴-Glu¹⁶¹. Both regions were capable of independently binding IgE upon placement into FcRIIa. Molecular modeling of the three-dimensional structure of FcRI-D2 has suggested that these binding regions correspond to the "exposed" C'-E and F-G loop regions at the membrane distal portion of the domain. A systematic site-directed mutagenesis strategy, whereby each residue in the Tyr¹²⁹-His¹³⁴ and Lys¹⁵⁴-Glu¹⁶¹ regions of FcRI was replaced with alanine, has identified key residues putatively involved in the interaction with IgE. Substitution of Tyr¹³¹, Glu¹³², Val¹⁵⁵, and Asp¹⁵⁹ decreased the binding of IgE, whereas substitution of Trp¹³⁰, Trp¹⁵⁶, Tyr¹⁶⁰, and Glu¹⁶¹ increased binding. In addition, mutagenesis of residues Trp¹¹³, Val¹¹⁵, and Tyr¹¹⁶ in the B-C loop region, which lies adjacent to the C'-E and F-G loops, has suggested Trp¹¹³ also contributes to IgE binding, since the substitution of this residue with alanine dramatically reduces binding. This information should prove valuable in the design of strategies to intervene in the FcRI-IgE interaction for the possible treatment of IgE-mediated allergic disease.

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