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

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.