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<p>MyD88 plays a pivotal role in Toll-like receptor (TLR) and interleukin-1 family signaling through its oligomerization upon receptor activation, leading to downstream protein recruitment. The Toll/interleukin-1 receptor domain of MyD88 (TIR<sub>MyD88</sub>) is responsible for this receptor-mediated oligomerization, but the detailed mechanism involved remains elusive. Here we investigate the structure of TIR<sub>MyD88</sub> oligomers and their interactions with TLRs. Cryoelectron microscopy reveals that tandemly arrayed TIR<sub>MyD88</sub> subunits form an antiparallel double-stranded filament that can further form rings and cylindrical filaments. Moreover, the self-assembly of TIR<sub>MyD88</sub> in vitro is markedly accelerated by dimeric rather than monomeric receptor TIRs, possibly reflecting the signal initiation step in vivo. High-speed atomic force microscopy further captures the dynamic processes of oligomerization of TIR<sub>MyD88</sub>, in addition to its direct interaction with the receptor TIRs. These results reveal a regulatory mechanism of TIR<sub>MyD88</sub> oligomerization underlying the signal initiation step.</p>

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Structural Mechanism of Receptor-Triggered MyD88 Oligomeric Assembly in Innate Immune Signaling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月17日

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  • Kazuki Kasai,
  • Kayo Imamura,
  • Masatoshi Uno,
  • Shiho Nukui,
  • Naotaka Sekiyama,
  • Tomoko Miyata,
  • Fumiaki Makino,
  • Ryusei Yamada,
  • Yoshiki Takahashi,
  • Noriyuki Kodera,
  • Keiichi Namba,
  • Hidenori Ohnishi,
  • Akihiro Narita,
  • Hiroki Konno,
  • Hidehito Tochio

摘要

MyD88 plays a pivotal role in Toll-like receptor (TLR) and interleukin-1 family signaling through its oligomerization upon receptor activation, leading to downstream protein recruitment. The Toll/interleukin-1 receptor domain of MyD88 (TIRMyD88) is responsible for this receptor-mediated oligomerization, but the detailed mechanism involved remains elusive. Here we investigate the structure of TIRMyD88 oligomers and their interactions with TLRs. Cryoelectron microscopy reveals that tandemly arrayed TIRMyD88 subunits form an antiparallel double-stranded filament that can further form rings and cylindrical filaments. Moreover, the self-assembly of TIRMyD88 in vitro is markedly accelerated by dimeric rather than monomeric receptor TIRs, possibly reflecting the signal initiation step in vivo. High-speed atomic force microscopy further captures the dynamic processes of oligomerization of TIRMyD88, in addition to its direct interaction with the receptor TIRs. These results reveal a regulatory mechanism of TIRMyD88 oligomerization underlying the signal initiation step.