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

Author

Listed:
  • Ernest Y. Lee

    (University of California, Los Angeles)

  • Changsheng Zhang

    (The University of Texas at Austin
    Peking University)

  • Jeremy Di Domizio

    (Lausanne University Hospital CHUV)

  • Fan Jin

    (University of Science and Technology of China)

  • Will Connell

    (University of California, Los Angeles)

  • Mandy Hung

    (University of California, Los Angeles)

  • Nicolas Malkoff

    (University of California, Los Angeles)

  • Veronica Veksler

    (University of California, Los Angeles)

  • Michel Gilliet

    (Lausanne University Hospital CHUV)

  • Pengyu Ren

    (The University of Texas at Austin)

  • Gerard C. L. Wong

    (University of California, Los Angeles)

Abstract

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.

Suggested Citation

  • Ernest Y. Lee & Changsheng Zhang & Jeremy Di Domizio & Fan Jin & Will Connell & Mandy Hung & Nicolas Malkoff & Veronica Veksler & Michel Gilliet & Pengyu Ren & Gerard C. L. Wong, 2019. "Helical antimicrobial peptides assemble into protofibril scaffolds that present ordered dsDNA to TLR9," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08868-w
    DOI: 10.1038/s41467-019-08868-w
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    Cited by:

    1. Jiayang Xie & Min Zhou & Yuxin Qian & Zihao Cong & Sheng Chen & Wenjing Zhang & Weinan Jiang & Chengzhi Dai & Ning Shao & Zhemin Ji & Jingcheng Zou & Ximian Xiao & Longqiang Liu & Minzhang Chen & Jin , 2021. "Addressing MRSA infection and antibacterial resistance with peptoid polymers," Nature Communications, Nature, vol. 12(1), pages 1-13, December.

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