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

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.

Structural Mimicry in Microbial and Antimicrobial Amyloids.

The remarkable variety of microbial species of human pathogens and microbiomes generates significant quantities of secreted amyloids, which are structured protein fibrils that serve diverse functions related to virulence and interactions with the host. Human amyloids are associated largely with fatal neurodegenerative and systemic aggregation diseases, and current research has put forward the hypothesis that the interspecies amyloid interactome has physiological and pathological significance. Moreover, functional and molecular-level connections between antimicrobial activity and amyloid structures suggest a neuroimmune role for amyloids that are otherwise known to be pathological.

Rare by Natural Selection: Disulfide-Bonded Supramolecular Antimicrobial Peptides.

Human LL-37 is an antimicrobial peptide forming thermostable supramolecular fibrils that surround bacterial cells. The crystal structure of LL-37 bearing an I24C substitution of most buried position in the fibril revealed disulfide-bonded dimers that further assembled into a fibrillar structure of densely packed helices We further demonstrated the position-dependent controllable antibacterial activity of LL-37 I24C and other cysteine mutants, mediated by regulation of intermolecular disulfide bonds and their role in the formation of supramolecular structures. The morphology of the fibrils and their antibacterial mechanism of action might be dependent on their interactions with specific bacteria.

The Human LL-37(17-29) antimicrobial peptide reveals a functional supramolecular structure.

Here, we demonstrate the self-assembly of the antimicrobial human LL-37 active core (residues 17-29) into a protein fibril of densely packed helices. The surface of the fibril encompasses alternating hydrophobic and positively charged zigzagged belts, which likely underlie interactions with and subsequent disruption of negatively charged lipid bilayers, such as bacterial membranes. LL-37 correspondingly forms wide, ribbon-like, thermostable fibrils in solution, which co-localize with bacterial cells.