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

bioRxiv - Biophysics Pub Date : 2024-09-18 DOI:10.1101/2024.09.13.612588

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

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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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从单体到寡聚体：先天性免疫信号中受体触发 MyD88 组装的结构机制

MyD88在Toll样受体（TLR）和白细胞介素-1家族信号传导过程中发挥着关键作用，它在受体激活时会寡聚，从而导致下游蛋白的招募。MyD88的Toll/白细胞介素-1受体结构域（TIRMyD88）负责这种受体介导的寡聚化，但其中涉及的详细机制仍不清楚。我们研究了 TIRMyD88 寡聚体的结构及其与 TLR 的相互作用。冷冻电镜显示，串联排列的 TIRMyD88 亚基形成了反平行双链丝，并可进一步形成环状和圆柱状丝。此外，体外 TIRMyD88 的自组装在二聚体而非单体受体 TIR 的作用下明显加快，这可能反映了体内的信号启动步骤。高速原子力显微镜进一步捕捉到了 TIRMyD88 除了与受体 TIRs 直接相互作用外，还发生了寡聚化的动态过程。基于这些结果，揭示了信号起始步骤所依赖的 TIRMyD88 寡聚化的新型调控机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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bioRxiv - Biophysics

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