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bioRxiv · 10.1101/2022.01.08.475498

The Cryo-EM Structures of two Amphibian Antimicrobial Cross-β Amyloid Fibrils

Bücker, R.·Seuring, C.·Cazey, C.·Veith, K.·Garcia-Alai, M.·Grünewald, K.·Landau, M.
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Abstract

The amyloid-antimicrobial link hypothesis is based on antimicrobial properties found in human amyloids involved in neurodegenerative and systemic diseases, along with amyloidal structural properties found in antimicrobial peptides (AMPs) across kingdoms of life. Supporting this hypothesis, we here determined the fibril structure of two AMPs from amphibians, uperin 3.5 and aurein 3.3, by cryogenic electron microscopy (cryo-EM), revealing amyloid cross-{beta} fibrils of mated {beta}-sheets at atomic resolution. Uperin 3.5 displayed substantial polymorphism with a protofilament of two mated {beta}-sheets. The determined structure was a polymorph showing a 3-blade symmetrical propeller of nine peptides per fibril layer including tight {beta}-sheet interfaces. This cross-{beta} cryo-EM structure complements the cross- fibril conformation previously determined by a crystal structure, substantiating a secondary structure switch mechanism of uperin 3.5. The aurein 3.3 arrangement consisted of six peptides per fibril layer, all showing kinked {beta}-sheets allowing a rounded compactness of the fibril. The kinked {beta}-sheets are similar to LARKS (Low-complexity, Amyloid-like, Reversible, Kinked segments) found in human functional amyloids. The amyloidal properties of antimicrobial peptides shed light on a mechanism of regulation of animicrobial activity involving self-assembly and fibril morphological variations. Moreover, the known endurance of amyloid structures can provide a template for the design of sturdy antimicrobials.

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Bücker, R., Seuring, C., Cazey, C., Veith, K., Garcia-Alai, M., Grünewald, K., Landau, M.. 2022-01-09. The Cryo-EM Structures of two Amphibian Antimicrobial Cross-β Amyloid Fibrils. https://doi.org/10.1101/2022.01.08.475498

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