From Monomers to Oligomers: Structural Mechanism of Receptor-Triggered MyD88 Assembly in Innate Immune Signaling

Kasai, K.; Imamura, K.; Uno, M.; Sekiyama, N.; Miyata, T.; Makino, F.; Yamada, R.; Takahashi, Y.; Kodera, N.; Namba, K.; Ohnishi, H.; Narita, A.; Konno, H.; Tochio, H.

doi:10.1101/2024.09.13.612588

bioRxiv · 10.1101/2024.09.13.612588

From Monomers to Oligomers: Structural Mechanism of Receptor-Triggered MyD88 Assembly in Innate Immune Signaling

Kasai, K.·Imamura, K.·Uno, M.·Sekiyama, N.·Miyata, T.·Makino, F.·Yamada, R.·Takahashi, Y.·Kodera, N.·Namba, K.·Ohnishi, H.·Narita, A.·Konno, H.·Tochio, H.

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Abstract

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. We investigated the structure of TIRMyD88 oligomers and their interactions with TLRs. Cryoelectron microscopy revealed that tandemly arrayed TIRMyD88 subunits formed an antiparallel double-stranded filament that could further form rings and cylindrical filaments. Moreover, the self-assembly of TIRMyD88 in vitro was markedly accelerated by dimeric rather than monomeric receptor TIRs, possibly reflecting the signal initiation step in vivo. High-speed atomic force microscopy further captured the dynamic processes of oligomerization of TIRMyD88, in addition to its direct interaction with the receptor TIRs. Based on these results, a novel regulatory mechanism of TIRMyD88 oligomerization underlying the signal initiation step was revealed.

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Kasai, K., Imamura, K., Uno, M., Sekiyama, N., Miyata, T., Makino, F., Yamada, R., Takahashi, Y., Kodera, N., Namba, K., Ohnishi, H., Narita, A., Konno, H., Tochio, H.. 2024-09-18. From Monomers to Oligomers: Structural Mechanism of Receptor-Triggered MyD88 Assembly in Innate Immune Signaling. https://doi.org/10.1101/2024.09.13.612588

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