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

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Auteurs
Date

4 mars 2019

Type de document
Périmètre
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Identifiants
Source

Serveur académique Lausannois

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Ce document est lié à :
info:eu-repo/semantics/altIdentifier/doi/10.1038/s41467-019-08868-w

Ce document est lié à :
info:eu-repo/semantics/altIdentifier/pmid/30833557

Ce document est lié à :
info:eu-repo/semantics/altIdentifier/eissn/2041-1723

Ce document est lié à :
info:eu-repo/semantics/altIdentifier/urn/urn:nbn:ch:serval-BIB_CC4224CAC2B20

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Serveur Académique Lausannois

Organisation

Université de Lausanne et CHUV

Licences

info:eu-repo/semantics/openAccess , CC BY 4.0 , https://creativecommons.org/licenses/by/4.0/

Mots-clés 0

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

Sujets proches En

Deoxyribonucleic acid TNA (Nucleic acid) Desoxyribonucleic acid Thymonucleic acid Structures Edifices Halls Skill Abilities Talent Aptitude Talents Proficiency Skills

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E.Y. Lee et al., « Helical antimicrobial peptides assemble into protofibril scaffolds that present ordered dsDNA to TLR9. », Serveur académique Lausannois, ID : 10.1038/s41467-019-08868-w

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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.

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