IRAK-4: A New Drug Target in Inflammation, Sepsis, and Autoimmunity

Molecular interactions at the TLR4 signaling complex. Upon stimulation with LPS, IRAK and Tollip are recruited to the receptor complex comprising TLR4, MD-2, and CD14. Simultaneous binding of IRAK-1 and its upstream kinase IRAK-4 to MyD88 ensures efficient activating phosphorylation of IRAK-1, which is released from the complex after further autophosphorylation. An additional adapter, Mal, recruits IRAK-2 to the complex. See text for details. TIR, Toll-IL-1 receptor domain; DD, death domain; KD, kinase domain.