Natural Antimicrobial Peptides Self-assemble as α/β Chameleon Amyloids

Abstract

Amyloid protein fibrils and some antimicrobial peptides (AMPs) share biophysical and structural properties. This observation suggests that ordered self-assembly can act as an AMP-regulating mechanism, and, vice versa, that human amyloids play a role in host defense against pathogens, as opposed to their common association with neurodegenerative and systemic diseases. Based on previous structural information on toxic amyloid peptides, we developed a sequence-based bioinformatics platform and, led by its predictions, experimentally identified 14 fibril-forming AMPs (ffAMPs) from living organisms, which demonstrated cross-β and cross-α amyloid properties. The results support the amyloid-antimicrobial link. The high prevalence of ffAMPs produced by amphibians and marine creatures among other species suggests that they confer unique advantageous properties in distinctive environments, potentially providing stability and adherence properties. Most of the newly identified 14 ffAMPs showed lipid-induced and/or time-dependent secondary structure transitions in the fibril form, indicating structural and functional cross-α/β chameleons. Specifically, ffAMP cytotoxicity against human cells correlated with inherent or lipid-induced α-helical fibril structure. The findings raise hypotheses about the role of fibril secondary structure switching in regulation of processes, such as the transition between a stable storage conformation and an active state with toxicity against specific cell types.

Lipid Oxidation Controls Peptide Self-Assembly near Membranes

“…9,10 Recent cryoEM studies also identified cross-α fibril structures for a number of peptides. [11][12][13][14] The formation of peptide fibrils follows typical nucleation-elongation kinetics with a slow nucleation phase followed by a fast elongation and growth of the peptide oligomers into fibrillar aggregates (see Figure 1a). 15,16 Several studies suggested an α-helical peptide conformation as an intermediate toward β-sheet rich fibrils.…”

“…9,10 Recent cryoEM studies also identified cross-α fibril structures for a number of peptides. 11–14…”