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Functional Protein Fibrils in the Fight Against Pathogens

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Different organisms secrete proteins and peptides that self-assemble into ordered amyloid fibrils that carry various physiological roles. Their function as key virulence factors in microbes, has rendered them attractive candidates for structural characterization aimed at discovering novel antimicrobial therapeutics. In contrast to the vast structural information available on eukaryotic amyloids involved in neurodegenerative and systemic diseases or which serve specific physiological roles, high-resolution structural information on microbial amyloids is lacking, perhaps due to their polymorphic nature and relatively recent discovery. Our lab pioneered the atomic-level analysis of bacterial amyloids and other eukaryotic functional fibrils involved in cytotoxicity, biofilm structuring, and antibacterial activity, and uncovered novel morphologies, extending beyond the canonical amyloid cross- structural feature composed of tightly mated β-sheets (Tayeb-Fligelman et. al., Science 2017, Salinas et al., Nat Commun 2018, Perov et al., PLoS Pathogens 2019, Tayeb-Fligelman et al., Structure 2020, Salinas et. al., PNAS 2021 , Engelberg and Landau, Nat Commun 2020, and unpublished results). The findings include cross-α fibrils of stacked α-helices arranged in mated sheets, just as in cross-β fibrils, cross-a/β secondary structure polymorphism in the same sequence, and other densely packed helical fibrils with novel morphologies. The similar structures of biofilm-associated and human pathological amyloidogenic regions led to repurposing of anti-Alzheimer’s compounds to act against Salmonella biofilm. Moreover, the structural similarity implies on possible inter-species interactions that could have bearing on amyloid diseases by the creation of transmissible agents. We expect that a detailed molecular understanding of microbial amyloids and other functional fibrils will provide the foundation for understanding the etiology of and potential connection between microbial and human ‘amylomes’ in health and disease.

This talk is part of the Biophysical Seminars series.

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