%0 Journal Article %J Nature immunology %D 2003 %T Binding of the Drosophila cytokine Spätzle to Toll is direct and establishes signaling. %A Weber, Alexander N R %A Tauszig-Delamasure, Servane %A Hoffmann, Jules A %A Lelièvre, Eric %A Gascan, Hugues %A Ray, Keith P %A Morse, Mary A %A Imler, Jean-Luc %A Gay, Nicholas J %K Animals %K Drosophila %K Drosophila Proteins %K Insect Proteins %K Protein Binding %K Protein Structure, Tertiary %K Receptors, Cell Surface %K Signal Transduction %K Toll-Like Receptors %N 8 %P 794-800 %R 10.1038/ni955 %V 4 %X The extracellular protein Spätzle is required for activation of the Toll signaling pathway in the embryonic development and innate immune defense of Drosophila. Spätzle is synthesized as a pro-protein and is processed to a functional form by a serine protease. We show here that the mature form of Spätzle triggers a Toll-dependent immune response after injection into the hemolymph of flies. Spätzle specifically bound to Drosophila cells and to Cos-7 cells expressing Toll. Furthermore, in vitro experiments showed that the mature form of Spätzle bound to the Toll ectodomain with high affinity and with a stoichiometry of one Spätzle dimer to two receptors. The Spätzle pro-protein was inactive in all these assays, indicating that the pro-domain sequence, which is natively unstructured, acts to prevent interaction of the cytokine and its receptor Toll. These results show that, in contrast to the human Toll-like receptors, Drosophila Toll requires only an endogenous protein ligand for activation and signaling. %8 2003 Aug