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(17-29) correspondingly forms wide, ribbon-like, thermostable fibrils in solution, which co-localize with bacterial cells. Structure-guided mutagenesis analyses supports the role of self-assembly in antibacterial activity. LL-37(17-29) resembles, in sequence and in the ability to form amphipathic helical fibrils, the bacterial cytotoxic PSM alpha 3 peptide that assembles into cross-alpha amyloid fibrils. This argues helical, self-assembling, basic building blocks across kingdoms of life and points to potential structural mimicry mechanisms. The findings expose a protein fibril which performs a biological activity, and offer a scaffold for functional and durable biomaterials for a wide range of medical and technological applications. The human antibacterial and immunomodulatory peptide LL-37 is a hCAP-18 protein cleavage product that self-assembles. Here, the authors present the human and gorilla LL-37 (17-29) crystal structures, revealing a self-assembly of amphipathic helices into a densely packed and elongated hexameric structure with a central pore and mutagenesis experiments support the role of self-assembly for antibacterial activity.