4bv4
Structure and allostery in Toll-Spatzle recognition
Structural highlights
FunctionSPZ_DROME Component of the extracellular signaling pathway that establishes the dorsal-ventral pathway of the embryo. Three proteases; ndl, gd and snk process easter to create active easter. Active easter defines cell identities along the dorsal-ventral continuum by activating the spz ligand for the Tl receptor in the ventral region of the embryo. Spz C-106 in the hemolymph controls expression of the antifungal peptide Drosomycin (Drs) by acting as a ligand of Tl and inducing an intracellular signaling pathway.[1] [2] [3] [4] Publication Abstract from PubMedDrosophila Toll functions in embryonic development and innate immunity and is activated by an endogenous ligand, Spatzle (Spz). The related Toll-like receptors in vertebrates also function in immunity but are activated directly by pathogen-associated molecules such as bacterial endotoxin. Here, we present the crystal structure at 2.35-A resolution of dimeric Spz bound to a Toll ectodomain encompassing the first 13 leucine-rich repeats. The cystine knot of Spz binds the concave face of the Toll leucine-rich repeat solenoid in an area delineated by N-linked glycans and induces a conformational change. Mutagenesis studies confirm that the interface observed in the crystal structure is relevant for signaling. The asymmetric binding mode of Spz to Toll is similar to that of nerve growth factor (NGF) in complex with the p75 neurotrophin receptor but is distinct from that of microbial ligands bound to the Toll-like receptors. Overall, this study indicates an allosteric signaling mechanism for Toll in which ligand binding to the N terminus induces a conformational change that couples to homodimerization of juxtamembrane structures in the Toll ectodomain C terminus. Cytokine Spatzle binds to the Drosophila immunoreceptor Toll with a neurotrophin-like specificity and couples receptor activation.,Lewis M, Arnot CJ, Beeston H, McCoy A, Ashcroft AE, Gay NJ, Gangloff M Proc Natl Acad Sci U S A. 2013 Nov 26. PMID:24282309[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
