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TLR3 forms a highly organized cluster when bound to a poly(I:C) RNA ligand

Author

Listed:
  • Chan Seok Lim

    (Department of Life Sciences and POSTECH)

  • Yoon Ha Jang

    (Department of Life Sciences and POSTECH)

  • Ga Young Lee

    (Department of Life Sciences and POSTECH)

  • Gu Min Han

    (Department of Life Sciences and POSTECH)

  • Hye Jin Jeong

    (Institute of Membrane Proteins, POSTECH)

  • Ji Won Kim

    (Department of Life Sciences and POSTECH
    Institute of Membrane Proteins, POSTECH)

  • Jie-Oh Lee

    (Department of Life Sciences and POSTECH
    Institute of Membrane Proteins, POSTECH)

Abstract

Toll-like Receptor 3 (TLR3) initiates a potent anti-viral immune response by binding to double-stranded RNA ligands. Previous crystallographic studies showed that TLR3 forms a homodimer when bound to a 46-base pair RNA ligand. However, this short RNA fails to initiate a robust immune response. To obtain structural insights into the length dependency of TLR3 ligands, we determine the cryo-electron microscopy structure of full-length TLR3 in a complex with a synthetic RNA ligand with an average length of ~400 base pairs. In the structure, the dimeric TLR3 units are clustered along the double-stranded RNA helix in a highly organized and cooperative fashion with a uniform inter-dimer spacing of 103 angstroms. The intracellular and transmembrane domains are dispensable for the clustering because their deletion does not interfere with the cluster formation. Our structural observation suggests that ligand-induced clustering of TLR3 dimers triggers the ordered assembly of intracellular signaling adaptors and initiates a robust innate immune response.

Suggested Citation

  • Chan Seok Lim & Yoon Ha Jang & Ga Young Lee & Gu Min Han & Hye Jin Jeong & Ji Won Kim & Jie-Oh Lee, 2022. "TLR3 forms a highly organized cluster when bound to a poly(I:C) RNA ligand," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34602-0
    DOI: 10.1038/s41467-022-34602-0
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    References listed on IDEAS

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    1. Oliver Schulz & Sandra S. Diebold & Margaret Chen & Tanja I. Näslund & Martijn A. Nolte & Lena Alexopoulou & Yasu-Taka Azuma & Richard A. Flavell & Peter Liljeström & Caetano Reis e Sousa, 2005. "Toll-like receptor 3 promotes cross-priming to virus-infected cells," Nature, Nature, vol. 433(7028), pages 887-892, February.
    2. Lena Alexopoulou & Agnieszka Czopik Holt & Ruslan Medzhitov & Richard A. Flavell, 2001. "Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3," Nature, Nature, vol. 413(6857), pages 732-738, October.
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    Cited by:

    1. Kentaro Sakaniwa & Akiko Fujimura & Takuma Shibata & Hideki Shigematsu & Toru Ekimoto & Masaki Yamamoto & Mitsunori Ikeguchi & Kensuke Miyake & Umeharu Ohto & Toshiyuki Shimizu, 2023. "TLR3 forms a laterally aligned multimeric complex along double-stranded RNA for efficient signal transduction," Nature Communications, Nature, vol. 14(1), pages 1-8, December.

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