TLR3 forms a laterally aligned multimeric complex along double-stranded RNA for efficient signal transduction

  • Nat Commun. 2023 Jan 11;14(1):164. doi: 10.1038/s41467-023-35844-2.
Kentaro Sakaniwa  #  1 ,  Akiko Fujimura  #  1 ,  Takuma Shibata  #  2 ,  Hideki Shigematsu  3  4 ,  Toru Ekimoto  5 ,  Masaki Yamamoto  3 ,  Mitsunori Ikeguchi  5  6 ,  Kensuke Miyake  2 ,  Umeharu Ohto  7 ,  Toshiyuki Shimizu  8
Affiliations
  • 1. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
  • 2. Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
  • 3. RIKEN SPring-8 Center, 1-1-1 Kouto, Sayo, Hyogo, 679-5148, Japan.
  • 4. Structural Biology Division, Japan Synchrotron Radiation Research Institute, 1-1-1 Kouto, Sayo, Hyogo, 679-5198, Japan.
  • 5. Computational Life Science Laboratory, Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
  • 6. HPC- and AI-driven Drug Development Platform Division, Center for Computational Science, RIKEN, Yokohama, 230-0045, Japan.
  • 7. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. [email protected].
  • 8. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. [email protected].
  • # Contributed equally.
PMID: 36631495 DOI: 10.1038/s41467-023-35844-2
Abstract

Toll-like Receptor 3 (TLR3) is a member of the TLR family, which plays an important role in the innate immune system and is responsible for recognizing viral double-stranded RNA (dsRNA). Previous biochemical and structural studies have revealed that a minimum length of approximately 40-50 base pairs of dsRNA is necessary for TLR3 binding and dimerization. However, efficient TLR3 activation requires longer dsRNA and the molecular mechanism underlying its dsRNA length-dependent activation remains unknown. Here, we report cryo-electron microscopy analyses of TLR3 complexed with longer dsRNA. TLR3 dimers laterally form a higher multimeric complex along dsRNA, providing the basis for cooperative binding and efficient signal transduction.