MRGPRX2 D184 Engagement by Food and Pollen Allergens: A Computational Hypothesis for IgE-Independent Mast-Cell Activation

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INTRODUCTION: Some food and pollen allergic reactions, including anaphylaxis disproportionate to IgE titers, are not fully explained by IgE-mediated mechanisms. MRGPRX2, a polyspecific sensor of cationic ligands, mediates IgE-independent mast-cell degranulation and requires a salt bridge to aspartate D184. Whether protein allergens can adopt D184-engaging poses is unknown. METHODS: Eleven peach, cedar pollen, peanut, birch, and yam allergens were docked against the experimental MRGPRX2 cryo-EM structure (PDB 7VV6) with HADDOCK3 under 3 protocols. Three agonists calibrated a D184 salt-bridge consistency threshold, four size-matched non-allergen proteins probed the determinants of engagement, and in silico mutagenesis tested D184 dependence. RESULTS: Five allergens met a high-consistency threshold (≥2/3): Pru p 7, Cry j 7, Cry j 1, Pru p 3, and Ara h 6; Ara h 2 was moderate, and mature-chain Cry j 2 did not engage D184. Engagement was charge driven yet determined by a single accessible residue rather than net charge: HADDOCK score tracked the electrostatic term (ρ = 0.91) but not molecular weight (ρ = 0.27), the net-acidic Ara h 6 engaged through ARG4 while the net-neutral ubiquitin did not, and D184A abolished the salt bridge. Accordingly, size-matched non-allergen proteins presenting a surface lysine/arginine (ribonuclease A, carbonic anhydrase II) also formed genuine D184 salt bridges, whereas the acidic maltose-binding protein did not. CONCLUSION: Allergens presenting an accessible surface lysine or arginine can form the MRGPRX2 D184 salt bridge in agonist-like geometry, but engagement is governed by local cationic-residue accessibility rather than net charge or allergen identity - non-allergen proteins engage equally - so docking alone establishes neither specificity nor binding affinity, receptor activation, or clinical relevance. We propose a charge-based, exposure-gated hypothesis for experimental and clinical validation.

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