Helical antimicrobial peptides assemble into protofibril scaffolds that present ordered dsDNA to TLR9.

Détails

Ressource 1Télécharger: 30833557_BIB_CC4224CAC2B2.pdf (1776.49 [Ko])
Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_CC4224CAC2B2
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Helical antimicrobial peptides assemble into protofibril scaffolds that present ordered dsDNA to TLR9.
Périodique
Nature communications
Auteur(s)
Lee E.Y., Zhang C., Di Domizio J., Jin F., Connell W., Hung M., Malkoff N., Veksler V., Gilliet M., Ren P., Wong GCL
ISSN
2041-1723 (Electronic)
ISSN-L
2041-1723
Statut éditorial
Publié
Date de publication
04/03/2019
Peer-reviewed
Oui
Volume
10
Numéro
1
Pages
1012
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Résumé
Amphiphilicity in ɑ-helical antimicrobial peptides (AMPs) is recognized as a signature of potential membrane activity. Some AMPs are also strongly immunomodulatory: LL37-DNA complexes potently amplify Toll-like receptor 9 (TLR9) activation in immune cells and exacerbate autoimmune diseases. The rules governing this proinflammatory activity of AMPs are unknown. Here we examine the supramolecular structures formed between DNA and three prototypical AMPs using small angle X-ray scattering and molecular modeling. We correlate these structures to their ability to activate TLR9 and show that a key criterion is the AMP's ability to assemble into superhelical protofibril scaffolds. These structures enforce spatially-periodic DNA organization in nanocrystalline immunocomplexes that trigger strong recognition by TLR9, which is conventionally known to bind single DNA ligands. We demonstrate that we can "knock in" this ability for TLR9 amplification in membrane-active AMP mutants, which suggests the existence of tradeoffs between membrane permeating activity and immunomodulatory activity in AMP sequences.
Mots-clé
Anti-Infective Agents/chemistry, Anti-Infective Agents/immunology, Anti-Infective Agents/pharmacology, Antimicrobial Cationic Peptides/chemistry, Antimicrobial Cationic Peptides/pharmacology, Cell Death/drug effects, Cell Membrane/drug effects, Computer Simulation, DNA/chemistry, DNA/immunology, Humans, Immunologic Factors/chemistry, Immunologic Factors/immunology, Ligands, Macrophages/drug effects, Models, Molecular, Protein Conformation, alpha-Helical/physiology, Scattering, Radiation, Toll-Like Receptor 9/chemistry, Toll-Like Receptor 9/immunology, X-Ray Diffraction
Pubmed
Web of science
Open Access
Oui
Création de la notice
17/03/2019 16:50
Dernière modification de la notice
30/04/2021 7:14
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