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.

Alexander C. Y. Foo

Nuclear Magnetic Resonance Group

National Institute of Environmental Health Sciences

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

Alexander C. Y. Foo

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National Institute of Environmental Health Sciences

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

Nuclear Magnetic Resonance Group