Helical antimicrobial peptides assemble into protofibril scaffolds that present ordered dsDNA to TLR9
| Autor: | Ernest Y. Lee, Mandy Hung, Michel Gilliet, Changsheng Zhang, Veronica Veksler, Jeremy Di Domizio, Fan Jin, Will Connell, Pengyu Ren, Gerard C. L. Wong, Nicolas Malkoff |
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| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular Protein Conformation alpha-Helical 0301 basic medicine Molecular model Protein Conformation Mutant General Physics and Astronomy 02 engineering and technology Ligands Scattering chemistry.chemical_compound Anti-Infective Agents X-Ray Diffraction Models Scattering Radiation lcsh:Science Multidisciplinary Radiation Cell Death 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 Macrophages/drug effects Protein Conformation alpha-Helical/physiology Toll-Like Receptor 9/chemistry Toll-Like Receptor 9/immunology 021001 nanoscience & nanotechnology 3. Good health 0210 nano-technology 1.1 Normal biological development and functioning Science Antimicrobial peptides Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Cathelicidins Underpinning research Membrane activity Immunologic Factors Macrophages Cell Membrane alpha-Helical TLR9 Molecular General Chemistry DNA 030104 developmental biology chemistry Toll-Like Receptor 9 Nucleic acid Biophysics lcsh:Q Function (biology) Antimicrobial Cationic Peptides |
| Zdroj: | Nature communications, vol 10, iss 1 Nature Communications, Vol 10, Iss 1, Pp 1-10 (2019) Nature Communications Nature communications, vol. 10, no. 1, pp. 1012 |
| Popis: | 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. Amphihelical antimicrobial peptides (AMPs) are bactericidal host defense factors, but their function as immunomodulators is emerging. Here the authors show that several AMPs organize DNA into periodic nanocrystals by self-assembling into superhelical protofibril scaffolds, which potentiates DNA sensing by TLR9. |
| Databáze: | OpenAIRE |
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