EXTREME POLYMORPHISM IN AMYLOIDS FROM PATHOGENIC MICROBES

Amyloids are proteins that self-assemble into highly ordered fibrils, mostly known for their involvement in neurodegenerative diseases. Yet, numerous amyloids are functional and participate in dedicated physiological activities, for example as virulence determinants in microbes. We investigate the atomic structures of functional amyloids that encode and regulate these activities. We discovered unique amyloid-like structures, including, to our surprise, a structure of a full-length bacterial cross-alpha amyloid-like fibril revealing surprising departure from pathological amyloids in which beta-rich structures are central. The fibrils, of the PSMα3 peptide secreted by Staphylococcus aureus, are toxic to human cells, clarifying their involvement in pathogenicity (Tayeb-Fligelman et. al., Science 355(6327): 831-833; 2017). In contrast, amyloidogenic peptides involved in biofilm structuring share similar atomic structures with pathological amyloids, forming highly stable cross-beta structures that stabilize the biofilm matrix. Surprisingly, three fibrillating antibacterial peptides secreted by different organisms (bacteria, amphibian and human) exposed extremely polymorphic fibrous architectures, all markedly different from the cross-beta fibril. Given our results we predict that the structural and functional repertoire of functional amyloids is far more diverse than previously anticipated, providing a rich source of targets for antimicrobial drug discovery.