Abstract
The cytoplasmic Toll/interleukin-1 receptor (TIR) domains of IL-1 receptors (IL-1Rs) are evolutionally conserved and essential for transmitting signals. IL-1RAcP is a shared co-receptor in the IL-1R family for signaling. Its splicing form IL-1RAcPb contains a different TIR domain and is unable to transduce NF-κB signaling. Here, we determined crystal structures of TIR domains of IL-1RAcPb and other IL-1Rs including IL-18Rβ, IL-1RAPL2, and zebrafish SIGIRR (zSIGIRR). Structurally variant regions in the TIR domain important for signaling were revealed by structural comparisons. Taking advantage of the IL-1RAcP/IL-1RAcPb pair, we demonstrated that differential TIR domain determines signaling discrepancies between IL-1RAcP and IL-1RAcPb. We also proved the functional importance of two helices (αC and αD) in the structurally variable regions and pinpointed critical residues in αC and αD for signaling. These results collectively provide additional and important knowledge for fully understanding the molecular basis of IL-1R TIR domain in mediating signaling.