A native IgE in complex with profilin provides insights into allergen recognition and cross-reactivity

García-Ramírez, Benjamin; Mares-Mejía, Israel; Rodríguez-Hernández, Annia; Cano‐Sánchez, Patricia; Torres‐Larios, Alfredo; Ortega, Enrique; Rodrı́guez-Romero, Adela

doi:10.1038/s42003-022-03718-w

Cited by 10 publications

(9 citation statements)

References 51 publications

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“…The second and most significant result was that the IgE from pooled sera from latex- and maize-allergic patients showed higher binding with the double mutant (G98N-E128D) ( Figure 3 ), compared to the single mutant rZea m 12 E128D. This result agrees with our previous findings, where murine 2F5/IgE showed 56% recognition with the rZea m 12 double mutant [ 12 ]. We must emphasize that we used a pool of sera from allergic patients; in addition, the IgE antibodies of individuals are polyclonal and have a different epitope recognition repertoire [ 21 , 22 ].…”

Section: Discussionsupporting

confidence: 90%

“…Another significant result was that 2D10 showed increased binding for the mutant rZea m 12 E128D ( Figure 2 ). Therefore, D128 at the carboxyl-terminal α-helix 3 of profilins ( Figure 5 A), which we have demonstrated to be involved in IgE/2F5-binding to latex profilin (rHev b 8), is implicated in IgE cross-reactivity [ 12 ]. Additionally, these mAbs inhibited polyclonal antibodies (from allergic patients’ sera), 23% for 1B4 and 74% for 2D10.…”

Section: Discussionmentioning

confidence: 99%

“…A superposition of rZea m 12 on the Fab 2F5/IgE-rHev b 8 structure indicated differences in these amino acids: Hev b 8 has N98 and D128, while rZea m 12 has G98 and E128. Therefore, we generated two rZea m 12 mutants: E128D and the double mutant G98N-E128D, and evaluated the recognition with mAb 2F5/IgE, which resulted in 16% with the single rZea m 12 mutant, while the double mutant showed 56% IgE recognition, compared to rHev b 8 recognition [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Molecular Basis of Plant Profilins’ Cross-Reactivity

et al. 2023

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Profilins are ubiquitous allergens with conserved structural elements. Exposure to profilins from different sources leads to IgE-cross-reactivity and the pollen–latex–food syndrome. Monoclonal antibodies (mAbs) that cross-react with plant profilins and block IgE-profilin interactions are relevant for diagnosis, epitope mapping, and specific immunotherapy. We generated IgGs mAbs, 1B4, and 2D10, against latex profilin (anti-rHev b 8) that inhibit the interaction of IgE and IgG4 antibodies from sera of latex- and maize-allergic patients by 90% and 40%, respectively. In this study, we evaluated 1B4 and 2D10 recognition towards different plant profilins, and mAbs recognition of rZea m 12 mutants by ELISAs. Interestingly, 2D10 highly recognized rArt v 4.0101 and rAmb a 8.0101, and to a lesser extent rBet v 2.0101, and rFra e 2.2, while 1B4 showed recognition for rPhl p 12.0101 and rAmb a 8.0101. We demonstrated that residue D130 at the α-helix 3 in profilins, which is part of the Hev b 8 IgE epitope, is essential for the 2D10 recognition. The structural analysis suggests that the profilins containing E130 (rPhl p 12.0101, rFra e 2.2, and rZea m 12.0105) show less binding with 2D10. The distribution of negative charges on the profilins’ surfaces at the α-helices 1 and 3 is relevant for the 2D10 recognition, and that may be relevant to explain profilins’ IgE cross-reactivity.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular Basis of Plant Profilins’ Cross-Reactivity

et al. 2023

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“…Therefore, the heavy-light chain pairing was not necessarily the same as that present in vivo. Recently, two other PDB deposits reveal structures of complexes between murine IgE Fab and Hev b 8 (PDB codes: 7SBD and 7SBG) [ 82 ]. From these five structures of IgE in complex with allergen, we will focus on Der p 2 in complex with Fab from the hIgE mAb 2F10 (2F10 Fab) (Fig.…”

Section: X-ray Crystal Structure Of Hige Mab In Complex With An Allergenmentioning

confidence: 99%

Human Monoclonal IgE Antibodies—a Major Milestone in Allergy

Smith

Chruszcz

Chapman³

et al. 2022

Curr Allergy Asthma Rep

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Purpose of Review Bound to its high affinity receptor on mast cells and basophils, the IgE antibody molecule plays an integral role in the allergic reaction. Through interactions with the allergen, it provides the sensitivity and specificity parameters for cell activation and mediator release that produce allergic symptoms. Advancements in human hybridoma technologies allow for the generation and molecular definition of naturally occurring allergen-specific human IgE monoclonal antibodies. Recent Findings A high-resolution structure of dust mite allergen Der p 2 in complex with Fab of the human IgE mAb 2F10 was recently determined using X-ray crystallography. The structure reveals the fine molecular details of IgE 2F10 binding its 750 Å2 conformational epitope on Der p 2. Summary This review provides an overview of this major milestone in allergy, the first atomic resolution structure of an authentic human IgE epitope. The molecular insights that IgE epitopes provide will allow for structure-based design approaches to the development of novel diagnostics, antibody therapeutics, and immunotherapies.

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“…Local unfolding or other major conformational changes as those observed here ( Figure 2 ) would make the IgE recognition impossible if the respective epitopes are destroyed by the structural rearrangements. An example for this would be the α3 helix, which is a known epitope (PDB accession code 7SBG of a structurally highly homologous profilin allergen in complex with IgE) and indeed unfolds at lower pH in the cases of Bet v 2 and Amb a 8 ( 56 ).…”

Section: Discussionmentioning

confidence: 99%

pH-dependent structural diversity of profilin allergens determines thermal stability

et al. 2022

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The family of profilin allergens is a common class of proteins found in plants, viruses and various eukaryotes including mammals. Profilins are characterized by an evolutionary conserved structural fold, which is responsible for their cross-reactive nature of Immunoglobulin E (IgE) antibodies. Despite their high overall structural similarity, they exhibit substantial differences in their biophysical properties, such as thermal and pH stability. To understand the origin of these functional differences of Amb a 8, Art v 4 and Bet v 2, we performed constant pH molecular dynamics simulation in combination with Gaussian accelerated MD simulations. Depending on the respective protonation at different pH levels, we find distinct differences in conformational flexibility, which are consistent with experimentally determined melting temperatures. These variations in flexibility are accompanied by ensemble shifts in the conformational landscape and quantified and localized by residue-wise B-factors and dihedral entropies. These findings strengthen the link between flexibility of profilin allergens and their thermal stability. Thus, our results clearly show the importance of considering protonation dependent conformational ensembles in solution to elucidate biophysical differences between these structurally similar allergens.

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A native IgE in complex with profilin provides insights into allergen recognition and cross-reactivity

Cited by 10 publications

References 51 publications

Molecular Basis of Plant Profilins’ Cross-Reactivity

Molecular Basis of Plant Profilins’ Cross-Reactivity

Human Monoclonal IgE Antibodies—a Major Milestone in Allergy

pH-dependent structural diversity of profilin allergens determines thermal stability

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