Abstract
ABSTRACT
Background
Peanuts are among the most prevalent food allergens responsible for anaphylaxis, particularly in children. Allergic responses may be mitigated by disrupting molecular interactions between immunoglobulin-E (IgE) and its binding partners: peanut allergen (Ara h 2) and IgE receptors (FcεRIa). However, the structural dynamics of IgE upon engaging these factors are not yet fully elucidated.
Objective
To characterize how Ara h 2 and/or FcεRIα binding influence IgE flexibility and its interdomain communications.
Methods
The structural dynamics of full-length IgE in various unbound and bound states were examined by combining molecular dynamics (MD) simulations with cross-linking mass spectrometry (XLMS). Causal relationship between IgE domains were characterized to infer allosteric communication pathways, which were assessed through hydrogen-deuterium exchange mass spectrometry (HDX-MS).
Results
Non-canonical bent IgE conformations were identified. We demonstrate that FcεRIα binding immobilizes IgE predominantly by stabilizing and restricting Fc flexibility, whereas Ara h 2 binding induces specific conformational changes within the FcεRIα-binding region. Our results further suggest that the Cε domains retain sufficient freedom to enable causal dynamics by the Fabs in a binding-dependent manner, thereby modulating the receptor engagement potential of IgE. Notably, concurrent binding of Ara h 2 and FcεRIα to IgE shifts the allosteric communication between the Fabs and Fc regions from the Cε3 to Cε4 domain.
Conclusion
Our findings provide new insights into the dynamic regulation of IgE and its role in allergic responses. This could serve as a structural framework for understanding IgE signaling in peanut allergy and suggest potential targets for therapeutic interventions.
Key messages
IgE adopts non-canonical bent FcεRIα-bound conformations with unexpected interactions between Fabs and FcεRIα
More diverse IgE-Ara h 2 interactions were observed in the presence of FcεRIα, indicating receptor-mediated stabilization of alternative binding modes
Binding to Ara h 2 promotes a more compact Fc structure resembling the FcεRIα-bound state, suggesting antigen binding primes IgE for receptor interaction.
Allosteric signaling shifts depending on binding state: in Ara h 2-bound IgE, signaling is mediated through Cε3 and Cε4, whereas in FcεRIα-bound states, signaling shifts toward Cε4. Concurrent Ara h 2 and FcεRIα binding results in a “hub-dominated” network with fewer but stronger interdomain dependencies, integrating inputs from Fab movements.
Capsule summary
This study provides molecular insight into the cooperative mechanisms within IgE underlying allergic responses. The binding-dependent allostery highlights potential targets for reducing receptor activation and may inform development of more precise anti-IgE therapies for managing allergies.