The mast cell binding site on human immunoglobulin E.
Antibodies of the immunoglobulin E isotype sensitize mast cells and basophils for antigen-induced mediator release by binding through the Fc portion to a high-affinity receptor (Fc epsilon R1, Ka = 10(9)M-1) on the cell surface causing the clinical manifestations of type I hypersensitivity. As the amino acid sequence of the human epsilon chain is now known, attempts have been made to map the Fc epsilon R1 binding site on IgE to a fragment smaller than Fc epsilon using proteolytic cleavage products, none of which proved to be active. Cleavage between the C epsilon 2 and C epsilon 3 domains released two inactive fragments, suggesting that the junction between these segments could be important in receptor binding. This region is protected against protease digestion in the rat IgE complex with the receptor of rat basophilic leukaemia cells. Here we report the mapping of the mast cell receptor binding site on human IgE to a sequence of 76 amino acids at the C epsilon 2/C epsilon 3 junction. Recombinant peptides containing this sequence inhibit passive sensitization of skin mast cells in vivo and sensitize mast cells to degranulation by anti-IgE in vitro almost as efficiently as a myeloma IgE. Fragments containing the separate domains are inactive. Additional sequences are required for rapid assembly of fragments into disulphide-linked dimers, suggesting that a single chain can form the active site. In a three-dimensional model of the human Fc epsilon, the two identical segments are far apart. Each folds to generate a cleft between the C epsilon 2 and C epsilon 3 domains on the surface of the Fc epsilon. The docking of IgE on to mast cells could take place within this cleft.
D000595:Amino Acid Sequence; D000707:Anaphylaxis / Q000517:prevention & control; D001665:Binding Sites; D055598:Chemical Phenomena; D002621:Chemistry; D006801:Humans; D007073:Immunoglobulin E / Q000378:metabolism* / Q000494:pharmacology; D007141:Immunoglobulin Fc Fragments / Q000378:metabolism / Q000494:pharmacology; D007139:Immunoglobulin epsilon-Chains / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D008407:Mast Cells / Q000378:metabolism*; D008958:Models, Molecular; D009101:Multiple Myeloma / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012871:Skin Diseases / Q000517:prevention & control
D007141:Immunoglobulin Fc Fragments; D007139:Immunoglobulin epsilon-Chains; D011994:Recombinant Proteins; D007073:Immunoglobulin E