The article reports the crystal structure of the MyD88: IRAK4: IRAK2 death domain (DD) complex, revealing a left-handed helical oligomer with a unique hierarchical assembly mechanism. The complex consists of 6 MyD88, 4 IRAK4, and 4 IRAK2 DDs, forming a tower-shaped structure. The assembly is hierarchical, with MyD88 recruiting IRAK4, and the MyD88: IRAK4 complex recruiting IRAK2 or IRAK1. The helical oligomer provides a platform for phosphorylation and activation of IRAK kinases. Composite binding sites are essential for recruitment, and the specificity of Myddosome formation is determined by molecular complementarity and surface electrostatics. The structure offers insights into the signaling pathways of Toll-like receptors (TLRs) and interleukin receptors, and suggests a versatile mechanism for DD complex assembly and regulation in signal transduction. The study also highlights the conservation of helical oligomerization in Drosophila Toll signaling and other DD superfamily members.The article reports the crystal structure of the MyD88: IRAK4: IRAK2 death domain (DD) complex, revealing a left-handed helical oligomer with a unique hierarchical assembly mechanism. The complex consists of 6 MyD88, 4 IRAK4, and 4 IRAK2 DDs, forming a tower-shaped structure. The assembly is hierarchical, with MyD88 recruiting IRAK4, and the MyD88: IRAK4 complex recruiting IRAK2 or IRAK1. The helical oligomer provides a platform for phosphorylation and activation of IRAK kinases. Composite binding sites are essential for recruitment, and the specificity of Myddosome formation is determined by molecular complementarity and surface electrostatics. The structure offers insights into the signaling pathways of Toll-like receptors (TLRs) and interleukin receptors, and suggests a versatile mechanism for DD complex assembly and regulation in signal transduction. The study also highlights the conservation of helical oligomerization in Drosophila Toll signaling and other DD superfamily members.