The Interleukin 1 (IL-1) Receptor Accessory Protein Toll/IL-1 Receptor Domain

Abstract

The Toll/interleukin 1 (IL-1) receptor family plays an important role in both innate and adaptive immunity. Amino acids 527-534 as part of the loop close to the conserved box 3 are critical for recruitment of myeloid differentiation factor 88 and to a lesser extent for IL-1 responsiveness. Modeling suggests that native folding of the TIR domain may be approached by the responsive deletion mutants ⌬528 -534 and ⌬527-533, whereas the C-terminal ␤-strand and/or ␣-helix is displaced in the nonresponsive mutant ⌬527-534.

Interactive Sites in the MyD88 Toll/Interleukin (IL) 1 Receptor Domain Responsible for Coupling to the IL1β Signaling Pathway

“…Similar loss of signaling in other TIR-containing molecules such as MAL/TIRAP (25) and IL1RAcP (26,27) has been reported, indicating that the invariant proline in the BB loop of Box 2 in these molecules is one of the interactive sites for other TIR domain-containing proteins. In striking contrast, a similar mutation (P200H) in MyD88 TIR domain, tested within a range of input concentrations, did not change the dominant negative effect of MyD88 TIR on IL1␤-induced NFB reporter gene activation in 293T cells (Fig.…”

“…basis of the three-dimensional docking model developed herein, that this interactive site is complementary to the previously identified site composed of residues 527-534 within the EE loop of the IL1RAcP TIR domain (26,27). Despite its proximity to the interactive site, invariant Pro 200 of the MyD88 TIR domain does not play a role in IL1␤-induced signaling.…”

“…Development (26,27). Thus, our study identified a complementary site on the MyD88 TIR domain that contributes to its interaction with the IL1RAcP TIR domain.…”

“…We therefore postulate that the negatively charged "knob," partially composed of BB loop on the surface of the MyD88 TIR domain (Fig. 2B), fits into the positively charged lysine patch formed by residues 527, 530, and 532 of the IL1RAcP TIR domain previously identified by Radons et al (26,27) as essential for IL1␤ signaling.…”

“…charged residues identified previously in EE loop residues 527-534 (26,27). Thus, it is not surprising that the invariant Pro 200 is inconsequential for MyD88-ILRAcP interaction.…”