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.