Structure of IL-33 and its interaction with the ST2 and IL-1RAcP receptors--insight into heterotrimeric IL-1 signaling complexes.
Members of the interleukin-1 (IL-1) family of cytokines play major roles in host defense and immune system regulation in infectious and inflammatory diseases. IL-1 cytokines trigger a biological response in effector cells by assembling a heterotrimeric signaling complex with two IL-1 receptor chains, a high-affinity primary receptor and a low-affinity coreceptor. To gain insights into the signaling mechanism of the novel IL-1-like cytokine IL-33, we first solved its solution structure and then performed a detailed biochemical and structural characterization of the interaction between IL-33, its primary receptor ST2, and the coreceptor IL-1RAcP. Using nuclear magnetic resonance data, we obtained a model of the IL-33/ST2 complex in solution that is validated by small-angle X-ray scattering (SAXS) data and is similar to the IL-1beta/IL-1R1 complex. We extended our SAXS analysis to the IL-33/ST2/IL-1RAcP and IL-1beta/IL-1R1/IL-1RAcP complexes and propose a general model of the molecular architecture of IL-1 ternary signaling complexes.
Lingel
Andreas
A
Department of Protein Engineering, Genentech, South San Francisco, CA 94080, USA.
Weiss
Thomas M
TM
Niebuhr
Marc
M
Pan
Borlan
B
Appleton
Brent A
BA
Wiesmann
Christian
C
Bazan
J Fernando
JF
Fairbrother
Wayne J
WJ
D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D007375:Interleukin-1 / Q000737:chemistry / Q000378:metabolism*; D053577:Interleukin-1 Receptor Accessory Protein / Q000737:chemistry*; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction
C079241:IL1RL1 protein, human; C506536:IL33 protein, human; D007375:Interleukin-1; D053577:Interleukin-1 Receptor Accessory Protein; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D011956:Receptors, Cell Surface