The Human LL-37(17-29) Antimicrobial Peptide Reveals a Functional Supramolecular Nanostructure

Abstract

Protein fibrils that perform biological activities present attractive biomaterials. Here we demonstrate, by crystal structures, the self-assembly of the antibacterial human LL-37 active core (residues 17-29) into a stable structure 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-3717-29 correspondingly formed wide, ribbon-like, thermostable fibrils in solution, which co-localized with bacterial cells, and structure-guided mutagenesis analyses supported the role of self-assembly in antibacterial activity. LL-3717-29 resembled, in sequence and in the ability to form amphipathic helical fibrils, the bacterial cytotoxic PSMα3 peptide that assembles into cross-α amyloid fibrils. This suggests helical, self-assembling, basic building blocks across kingdoms of life and point to potential structural mimicry mechanisms. The findings offer a scaffold for functional and durable nanostructures for a wide range of medical and technological applications.