Three-dimensional structure and IgE-binding properties of mature fully active Der p 1, a clinically relevant major allergen

Halleux, S de; Stura, E.A.; VanderElst, Luc; Carlier, Vincent; Jacquemin, Marc; Saint-Remy, Jean-Marie

doi:10.1016/j.jaci.2005.11.032

Cited by 68 publications

(51 citation statements)

References 23 publications

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“…Distinguishing functional dimer interfaces from contacts that are artifacts of crystallization is a difficult task, because it is known that features such as hydrophobicity, hydrogen bonding, and amino acid composition vary widely in subunit interfaces (26). The x-ray crystal structure of a homodimer of mature recombinant Der p 1 has been reported, and the study suggested that dimerization under natural conditions contributed to allergenicity (27). However, we recently found that natural Der f 1 did not dimerize in crystals.…”

Section: Discussionmentioning

confidence: 95%

“…4 Whereas it was not possible to conclude unambiguously that the dimeric state of mature Der p 1 observed in crystals is physiologically relevant, Bla g 2 is predicted to be a dimer under physiological conditions. The dimer interface between Bla g 2 monomers is extensive (1139 Å 2 per monomer), above the consensus cut-off value (ϳ850 Å 2 ) that allows distinction between contacts caused by crystal packing and real physiological contacts, but it is only 620 Å 2 for Der p 1 (27).…”

Section: Discussionmentioning

confidence: 98%

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Crystal Structure of a Dimerized Cockroach Allergen Bla g 2 Complexed with a Monoclonal Antibody

Gustchina

Alexandratos

et al. 2008

Journal of Biological Chemistry

103

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The crystal structure of a 1:1 complex between the German cockroach allergen Bla g 2 and the Fab fragment of a monoclonal antibody 7C11 was solved at 2.8-Å resolution. Bla g 2 binds to the antibody through four loops that include residues 60 -70, 83-86, 98 -100, and 129 -132. Cation-interactions exist between Lys-65, Arg-83, and Lys-132 in Bla g 2 and several tyrosines in 7C11. In the complex with Fab, Bla g 2 forms a dimer, which is stabilized by a quasi-four-helix bundle comprised of an ␣-helix and a helical turn from each allergen monomer, exhibiting a novel dimerization mode for an aspartic protease. A disulfide bridge between C51a and C113, unique to the aspartic protease family, connects the two helical elements within each Bla g 2 monomer, thus facilitating formation of the bundle. Mutation of these cysteines, as well as the residues Asn-52, Gln-110, and Ile-114, involved in hydrophobic interactions within the bundle, resulted in a protein that did not dimerize. The mutant proteins induced less ␤-hexosaminidase release from mast cells than the wild-type Bla g 2, suggesting a functional role of dimerization in allergenicity. Because 7C11 shares a binding epitope with IgE, the information gained by analysis of the crystal structure of its complex provided guidance for site-directed mutagenesis of the allergen epitope. We have now identified key residues involved in IgE antibody binding; this information will be useful for the design of vaccines for immunotherapy.Cockroach allergy is associated with the development of asthma and is a risk factor for emergency room admission of asthmatic patients, especially among inner city children living in low-income houses infested with cockroaches (1, 2). Cockroaches release allergens to the environment, which are carried by particles (5-40 m of diameter) that reach the lung by inhalation. Bla g 2 is one of the most important cockroach allergens, eliciting production of specific IgE in ϳ70% of cockroach-allergic patients at exposure levels that are 10 -100-fold lower than those from other common indoor allergens from dust mite and cat (3-5). Exposure to Bla g 2 results in cross-linking of IgE bound to the surface of mast cells or basophils from sensitized patients (i.e. in immunological terms, cross-linking refers to the non-covalent linkages between the allergen and two IgE molecules at the surface of mast cells or basophils), and induces release of potent mediators (histamine, leukotrienes, prostaglandins, etc.) of allergic reactions.We recently solved the crystal structure of Bla g 2, confirming that the overall fold of this allergen corresponds to that of pepsin-like aspartic proteases, and revealing structural elements that explain why it is enzymatically inactive (6, 7). Bla g 2 contains important amino acid substitutions in the area corresponding to the catalytic site. These modifications impair enzymatic function, and the allergen did not show proteolytic activity in standard in vitro assays using casein and hemoglobin as substrates (7). Bla g 2 belongs to a gro...

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 98%

Crystal Structure of a Dimerized Cockroach Allergen Bla g 2 Complexed with a Monoclonal Antibody

Gustchina

Alexandratos

et al. 2008

Journal of Biological Chemistry

103

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“…In all of the 4C1 complexes, the allergen was monomeric. A dimeric form of the mature recombinant Der p 1 was reported previously (36). However, it was subsequently shown that the dimeric structure is unlikely to be physiologically relevant (15).…”

Section: Der P 1 and Der F 1 In Complex With 4c1-complexes Of Mabmentioning

confidence: 88%

Molecular Determinants for Antibody Binding on Group 1 House Dust Mite Allergens

Chruszcz

Pomés

Glesner

et al. 2012

Journal of Biological Chemistry

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“…Allergic individuals, who showed enhanced histamine release by addition of cystatin A, might be sensitized to such IgE epitopes stably structured by binding of cystatin A. Recently, a research group reported that mature Der p 1 forms a homodimer in crystals and speculated that the homodimer might also be formed in solution on the basis of their observation that Der p 1 showed abnormal behavior in an analysis with size exclusion gel chromatography (22). The interface of the homodimer overlaps with the binding site for cystatin A and therefore another possible explanation for the enhancement of histamine-releasing activity could be that the binding of cystatin A prevented the homodimer from forming.…”

Section: Discussionmentioning

confidence: 99%

“…IgE epitopes of Der f 1 and Der p 1 are dependent on the integrity of the conformational structure (8, 16 -19), and high cross-reactivity between Der f 1 and Der p 1 has been reported (9,11,19,20). The crystal structures of the Der p 1 precursor (21) and mature Der p 1 (22) were determined.…”

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confidence: 99%

Modulation of Allergenicity of Major House Dust Mite Allergens Der f 1 and Der p 1 by Interaction with an Endogenous Ligand

Takai¹,

Kato²,

Hatanaka

et al. 2009

The Journal of Immunology

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Although many allergens bind endogenous molecules other than Abs in the human body, whether the interaction can modulate allergenicity has been unknown. Here, we investigated the effect of the interaction of recombinant major mite group 1 allergens (Der f 1 and Der p 1), which belong to the papain-like cysteine protease family, with an endogenous protease inhibitor, cystatin A, on their allergenicity. Cystatin A bound reduced forms of the allergens, in which the cysteine residue at the catalytic center of the protease activity was reduced by treatment with l-cysteine, but did not bind oxidized forms. Cystatin A partially inhibited the binding of IgE in mite-allergic volunteers’ sera to the reduced forms, but unexpectedly enhanced the basophil histamine-releasing activity. A catalytic site-mutant of Der f 1 behaved in terms of histamine release, similarly to the reduced form. Molecular modeling showed that cystatin A interacts with the allergens within a narrow area. The results indicate that interaction with cystatin A reduces the limited number of IgE epitopes of the allergens but enhances their biological activity to release histamine, suggesting a new concept, that interaction between allergens and their endogenous ligands modulates the allergenicity even toward enhancement in the effector phase. On the other hand, i.p. immunization without alum of mice with cystatin A-treated reduced Der f 1 induced less serum Der f 1-specific IgE than immunization with reduced Der f 1 alone, suggesting that endogenous protease inhibitors suppress the induction of allergen-specific IgE, which is dependent on the enzymatic activity of cysteine protease-allergens, in the sensitization process.

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Three-dimensional structure and IgE-binding properties of mature fully active Der p 1, a clinically relevant major allergen

Cited by 68 publications

References 23 publications

Crystal Structure of a Dimerized Cockroach Allergen Bla g 2 Complexed with a Monoclonal Antibody

Crystal Structure of a Dimerized Cockroach Allergen Bla g 2 Complexed with a Monoclonal Antibody

Molecular Determinants for Antibody Binding on Group 1 House Dust Mite Allergens

Modulation of Allergenicity of Major House Dust Mite Allergens Der f 1 and Der p 1 by Interaction with an Endogenous Ligand

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