From Monomers to Oligomers: Structural Mechanism of Receptor-Triggered MyD88 Assembly in Innate Immune Signaling
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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. We investigated the structure of TIR MyD88 oligomers and their interactions with TLRs. Cryoelectron microscopy revealed that tandemly arrayed TIR MyD88 subunits formed an antiparallel double-stranded filament that could further form rings and cylindrical filaments. Moreover, the self-assembly of TIR MyD88 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 TIR MyD88 , in addition to its direct interaction with the receptor TIRs. Based on these results, a novel regulatory mechanism of TIR MyD88 oligomerization underlying the signal initiation step was revealed.
