MyD88 self-assembles into supramolecular filaments to amplify NF-κB signaling

MyD88 is a central player in innate immunity. The molecular mechanism of MyD88 mutation-related diseases largely remains elusive. Here, we report that MyD88 self-assembles into high-order supramolecular structures as a signal amplification machinery. We show that the combination of the death domain (MyD88 DD ) and the intermediate domain (MyD88 ID ) is the minimum unit for the filament formation, which is modulated by the TIR domain (MyD88 TIR ). The loss-of-function mutant L93P disrupts the filaments; the gain-of-function mutant L252P transforms the filaments into speckles. Atomic molecular dynamics simulations demonstrate that the L93P mutation induces conformational changes of MyD88 DD by disrupting its hydrophobic core. The L252P mutation causes the unfolding of an α-helix between residues 246–252 and more exposure of the BB-loop. These pathologically relevant mutations alter the MyD88 assembly structure and function, which may contribute to a variety of disease development processes.