Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 290, Issue 36, Pages 22111-22126Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.675066
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Funding
- Deutsche Forschungsgemeinschaft [EXC114, SFB 594]
- Bavarian Ministry of Sciences, Research, and the Arts in the framework of the Bavarian Molecular Biosystems Research Network
- Alexander von Humboldt Foundation
- EMBO Long Term Fellowship
- Schrodinger Fellowship by the Austrian Science Fund
- APART Fellowship from the Austrian Academy of Sciences
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The IL-4-inducing principle from Schistosoma mansoni eggs (IPSE/alpha-1), the major secretory product of eggs from the parasitic worm S. mansoni, efficiently triggers basophils to release the immunomodulatory key cytokine interleukin-4. Activation by IPSE/alpha-1 requires the presence of IgE on the basophils, but the detailed molecular mechanism underlying activation is unknown. NMR and crystallographic analysis of IPSE Delta NLS, a monomeric IPSE/alpha-1 mutant, revealed that IPSE/alpha-1 is a new member of the beta gamma-crystallin superfamily. We demonstrate that this molecule is a general immunoglobulin-binding factor with highest affinity for IgE. NMR binding studies of IPSE Delta NLS with the 180-kDa molecule IgE identified a large positively charged binding surface that includes a flexible loop, which is unique to the IPSE/alpha-1 crystallin fold. Mutational analysis of amino acids in the binding interface showed that residues contributing to IgE binding are important for IgE-dependent activation of basophils. As IPSE/alpha-1 is unable to cross-link IgE, we propose that this molecule, by taking advantage of its unique IgE-binding crystallin fold, activates basophils by a novel, cross-linking-independent mechanism.
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