The Amphibian Antimicrobial Peptide Uperin 3.5 is a Cross-α/Cross-β Chameleon Functional Amyloid

Antimicrobial activity is being increasingly linked to amyloid fibril formation, suggesting physiological roles for some human amyloids, which have historically been viewed as strictly pathological agents. This work reports on formation of functional cross-α amyloid fibrils of the amphibian antimicrobial peptide uperin 3.5 at atomic-resolution, an architecture initially discovered in the bacterial PSMα3 cytotoxin. The fibrils of uperin 3.5 and PSMα3 were comprised of parallel and anti-parallel helical sheets, respectively, recapitulating properties of β-sheets. Uperin 3.5 helical fibril formation was largely induced by, and formed on, bacterial cells or membrane mimetics, and led to membrane damage and cell death. Uperin 3.5 demonstrated chameleon properties, with a secondary structure switch to cross-β fibrils with reduced antibacterial activity in the absence of lipids or after heat shock. These findings suggest a regulation mechanism, which includes storage of inactive peptides as well as environmentally induced activation of uperin 3.5, via chameleon cross-α/β amyloid fibrils.