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 MyD88 ) is responsible for this receptor-mediated oligomerization, but the detailed mechanism involved remains elusive. Here we investigate the structure of TIR MyD88 oligomers and their interactions with TLRs. Cryoelectron microscopy reveals that tandemly arrayed TIR MyD88 subunits form an antiparallel double-stranded filament that can further form rings and cylindrical filaments. Moreover, the self-assembly of TIR MyD88 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 MyD88 , in addition to its direct interaction with the receptor TIRs. These results reveal a regulatory mechanism of TIR MyD88 oligomerization underlying the signal initiation step.
Kasai et al. (Fri,) studied this question.
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