Structural determinants of odorant-binding proteins affecting their ability to form amyloid fibrils

The formation of amyloid fibrils is associated with many severe pathologies as well as the execution of essential physiological functions by proteins. Despite the diversity, all amyloids share a similar morphology and consist of stacked β-strands, suggesting high amyloidogenicity of native proteins enriched with β-structure. Such proteins include those with a β-barrel-like structure with β-strands arranged into a cylindrical β-sheet. However, the mechanisms responsible for destabilization of the native state and triggering fibrillogenesis have not thoroughly explored yet. Here we analyze the structural determinants of fibrillogenesis in proteins with β-barrel structures on the example of odorant-binding protein (OBP), whose amyloidogenicity was recently demonstrated in vitro. We reveal a crucial role in the fibrillogenesis of OBPs for the "open" conformation of the molecule. This conformation is achieved by disrupting the interaction between the β-barrel and the C-terminus of protein monomers or dimers, which exposes "sticky" amyloidogenic sites for interaction. The data suggest that the "open" conformation of OBPs can be induced by destabilizing the native β-barrel structure through the disruption of: 1) intramolecular disulfide cross-linking and non-covalent contacts between the C-terminal fragment and β-barrel in the protein's monomeric form, or 2) intermolecular contacts involved in domain swapping in the protein's dimeric form.