removal-replacement-endogenous-ligands-from-lipid-bound-proteins

Removal and Replacement of Endogenous Ligands from Lipid-Bound Proteins and Allergens

Many major allergens bind to hydrophobic lipid-like molecules, including Mus m 1, Bet v 1, Der p 2, and Fel d 1. These ligands are strongly retained and ...

National Institute of Environmental Health Sciences

Allergen-antibody complexes are extremely valuable in describing the detailed molecular features of epitopes. This review summarizes insights gained from recently published co-structures and what obstacles impede the acquisition of further data.

Structural Analysis of Recent Allergen-Antibody Complexes and Future Directions.

Are allergens more abundant and/or more stable than other proteins in pollens and dust?

The cockroach allergen Bla g 1 forms a novel fold consisting of 12 amphipathic alpha-helices enclosing an exceptionally large hydrophobic cavity which was previously demonstrated to bind a variety of lipids. Since lipid-dependent immunoactivity is observed in numerous allergens, understanding the structural basis of this interaction could yield insights into the molecular determinants of allergenicity. Here, we report atomic modelling of Bla g 1 bound to both fatty-acid and phospholipids ligands, with 8 acyl chains suggested to represent full stoichiometric binding. This unusually high occupancy was verified experimentally, though both modelling and circular dichroism indicate that the general alpha-helical structure is maintained regardless of cargo loading. Fatty-acid cargoes significantly enhanced thermostability while inhibiting cleavage by cathepsin S, an endosomal protease essential for antigen processing and presentation; the latter of which was found to correlate to a decreased production of known T-cell epitopes. Both effects were strongly dependent on acyl chain length, with 18-20 carbons providing the maximal increase in melting temperature (~20 °C) while completely abolishing proteolysis. Diacyl chain cargoes provided similar enhancements to thermostability, but yielded reduced levels of proteolytic resistance. This study describes how the biophysical properties of Bla g 1 ligand binding and digestion may relate to antigen processing, with potential downstream implications for immunogenicity.

Article	Year
Structural Analysis of Recent Allergen-Antibody Complexes and Future Directions. Current allergy and asthma reports\| PubMed ID: 30815753	2019
Are allergens more abundant and/or more stable than other proteins in pollens and dust? Allergy\| PubMed ID: 31749155	2020
Hydrophobic ligands influence the structure, stability, and processing of the major cockroach allergen Bla g 1. Scientific reports\| PubMed ID: 31797892	2019

Alexander C. Y. Foo

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