The “universal adaptor” protein MyD88 orchestrates innate immunity by propagating signals from receptor proteins called TLRs and IL-1Rs.Specifically, activation of these receptors enables MyD88-dependent formation of an organizing center known as the myddosome. An alternate form of MyD88 lacking the intermediate domain (ID), MyD88S, can silence the immune response, but the mechanism isn’t well understood. To learn more, researchers recently investigated the functions of MyD88 variants and mutants in cells and with computer programs. They found that the variant MyD88S is recruited to the newly forming myddosome, where it inhibits further myddosome maturation by preventing incorporation of additional components. In normal MyD88, the ID doesn’t have a well-defined secondary structure, but the amino acid tyrosine at site 116 is required for myddosome formation and related signaling. Although confirmation is needed, the results clarify the importance of the ID in MyD88 and reveal how the ID-lacking variant MyD88S exerts its negative effects, providing insights into the mechanisms of innate immune activation and inhibition.