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The immunoglobulin-like modules Cε3 and α2 are the minimal units necessary for human IgE-FcεRI interaction
Luca Vangelista, … , Annalisa Pastore, Rudolf Valenta
Luca Vangelista, … , Annalisa Pastore, Rudolf Valenta
Published June 1, 1999
Citation Information: J Clin Invest. 1999;103(11):1571-1578. https://doi.org/10.1172/JCI6551.
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The immunoglobulin-like modules Cε3 and α2 are the minimal units necessary for human IgE-FcεRI interaction

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Abstract

Atopic allergy is a genetically determined immunodisorder that affects almost 20% of the population worldwide. Immediate symptoms of type I allergy are caused by the release of biologic mediators from effector cells induced by IgE-allergen complexes that cross-link the high-affinity receptor for IgE (FcεRI). Chronic disease manifestations result from allergen-specific T-cell activation, a process that is enhanced when allergens are presented via FcεRI-bound IgE. We report the baculovirus expression, as soluble recombinant proteins, of the minimal units required for human IgE and FcεRI interaction: Cε3 represents the third constant domain of the IgE heavy chain, and α2 is the membrane-proximal Ig-like module from FcεRIα. Native overlay experiments showed binding of human FcεRIα to recombinant Cε3 and of natural or recombinant human IgE to recombinant α2. Moreover, recombinant Cε3 inhibited binding of natural IgE antibodies to α2, and preincubation of human IgE with α2 inhibited anti-IgE–triggered histamine release from human basophils. Isolated Cε3 and α2 can now be used for the molecular and structural analysis of the IgE-FcεRI interaction, as well as for diagnostic and therapeutic applications.

Authors

Luca Vangelista, Sylvia Laffer, Robert Turek, Hans Grönlund, Wolfgang R. Sperr, Peter Valent, Annalisa Pastore, Rudolf Valenta

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Figure 1

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(a) FcεRIα1-2 and α2 multiple sequence alignment, secondary structure, a...
(a) FcεRIα1-2 and α2 multiple sequence alignment, secondary structure, and solvent accessibility prediction. The top 3 lines represent α2, α1-2, and α-chain constructs, respectively. The consensus line derives from a Gonnet pam250 matrix in which asterisks represent fully conserved residues, and columns and dots represent, respectively, strong and weak groups of conserved residues (defined in ref. 45); after the double virgule (//), FCE2_RAT is not considered for the consensus. Each sequence is preceded by its SwissProt database’s identification entry name. Hyphens in the sequences indicate gaps. Sequences are colored to illustrate conservation of features in addition to amino acid identity. All glycines and prolines are colored in orange and yellow, respectively. Other residues are colored according to conservation of their physicochemical properties (purple, acidic; blue, hydrophobic; light blue, hydrophobic tendency; red, basic; green, hydrophilic; white, unconserved). The last 3 lines indicate the predicted secondary structure (SecStrPred), the predicted solvent accessibility (accessibility), both according to the PHD program and a numbering reference (ruler). In the secondary structure prediction, uppercase letters are used for positions where accuracy exceeds 86%, and the overall accuracy of the prediction is 72%. E indicates residue in predicted β strand. In the solvent accessibility prediction, uppercase letters are used for residues where accuracy exceeds 69%, and the overall accuracy of the prediction is 54%. A and B indicate exposed and buried residues, respectively. (b) Cε3 multiple sequence alignment, secondary structure, and solvent accessibility prediction. The top 3 lines represent Cε3I, Cε3II, and Cε3III constructs, respectively. Each sequence is preceded by its SwissProt or SPTREMBLNEW database’s identification entry name. SecCgamma2 line represents the secondary structure content of the Cγ2 module of IgG1, for which the three-dimensional structure is known (31). E indicates residue in β strand. Consensus, SecStrPred, accessibility and ruler lines, hyphens, and color code are as in a. (c) Ribbon representation of the immunoglobulin fold as modeled for Cε3 on the coordinates of 1fc1. The fold belongs to the C1 immunoglobulin subfamily. The 2 sheets are colored differently. The NH2- and COOH-termini (N and C, respectively) are indicated near the corresponding strand.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 6 patents
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