Structural Mechanism of Receptor-Triggered MyD88 Oligomeric Assembly in Innate Immune Signaling.
basic_science · Level V
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- Record sourced from PubMed, PMID 41997963.
- Also identified by DOI 10.1038/s41467-026-71836-8.
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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 (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.