The structure of the antimicrobial human cathelicidin LL-37 shows oligomerization and channel formation in the presence of membrane mimics

Enea Sancho-Vaello, David Gil-Carton, Patrice François, Eve Julie Bonetti, Mohamed Kreir, Karunakar Reddy Pothula, Ulrich Kleinekathöfer, Kornelius Zeth*

*Corresponding author

Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

Abstract

The human cathelicidin LL-37 serves a critical role in the innate immune system defending bacterial infections. LL-37 can interact with molecules of the cell wall and perforate cytoplasmic membranes resulting in bacterial cell death. To test the interactions of LL-37 and bacterial cell wall components we crystallized LL-37 in the presence of detergents and obtained the structure of a narrow tetrameric channel with a strongly charged core. The formation of a tetramer was further studied by cross-linking in the presence of detergents and lipids. Using planar lipid membranes a small but defined conductivity of this channel could be demonstrated. Molecular dynamic simulations underline the stability of this channel in membranes and demonstrate pathways for the passage of water molecules. Time lapse studies of E. coli cells treated with LL-37 show membrane discontinuities in the outer membrane followed by cell wall damage and cell death. Collectively, our results open a venue to the understanding of a novel AMP killing mechanism and allows the rational design of LL-37 derivatives with enhanced bactericidal activity.

OriginalsprogEngelsk
Artikelnummer17356
TidsskriftScientific Reports
Vol/bind10
Udgave nummer1
ISSN2045-2322
DOI
StatusUdgivet - 1 dec. 2020

Bibliografisk note

Funding Information:
We would like to thank Sandra Delgado for the technical help in the preparation of the cryoEM vitrified grids and Barnaby Searle for the diligent proofreading of this paper. Funding was provided by the Unidad de Biofisica and the IKERBASQUE and MINECO science foundations.

Publisher Copyright:
© 2020, The Author(s).

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