High-resolution structure of murine interleukin 1 homologue IL-1F5 reveals unique loop conformations for receptor binding specificity.
Interleukin-1 (IL-1) F5 is a novel member of the IL-1 family. The IL-1 family are involved in innate immune responses to infection and injury. These cytokines bind to specific receptors and cause activation of NFkappaB and MAP kinase. IL-1F5 has a sequence identity of 44% to IL-1 receptor antagonist (IL-1Ra), a natural antagonist of the IL-1 system. Here we report the crystal structure of IL-1F5 to a resolution of 1.6 A. It has the same beta-trefoil fold as other IL-1 family members, and the hydrophobic core is well conserved. However, there are substantial differences in the loop conformations, structures that confer binding specificity for the cognate receptor to IL-1beta and the antagonist IL-1Ra. Docking and superimposition of the IL-1F5 structure suggest that is unlikely to bind to the interleukin1 receptor, consistent with biochemical studies. The structure IL-1F5 lacks features that confer antagonist properties on IL-1Ra, and we predict that like IL-1beta it will act as an agonist. These studies give insights into how distinct receptor specificities can evolve within related cytokine families.
Dunn
Eleanor F
EF
Department of Biochemistry, Trinity College, Dublin 2, Ireland.
Gay
Nicholas J
NJ
Bristow
Adrian F
AF
Gearing
David P
DP
O'Neill
Luke A J
LA
Pei
Xue Yuan
XY
D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012795:Sialoglycoproteins / Q000737:chemistry
D016207:Cytokines; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; C478197:Il36rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D008024:Ligands; D012795:Sialoglycoproteins