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Cytokine Spatzle binds to the Drosophila immunoreceptor Toll with a neurotrophin-like specificity and couples receptor activation

DOI: 10.1073/pnas.1317002110 DOI Help
PMID: 24282309 PMID Help

Authors: Miranda Lewis (University of Cambridge) , C. J. Arnot (University of Cambridge) , H. Beeston (University of Leeds) , A. Mccoy (University of Cambridge) , A. E. Ashcroft (University of Leeds) , N. J. Gay (University of Cambridge) , Monique Gangloff (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 110 (51) , PAGES 20461 - 20466

State: Published (Approved)
Published: December 2013

Abstract: Drosophila Toll functions in embryonic development and innate immunity and is activated by an endogenous ligand, Spätzle (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-Å 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.

Journal Keywords: Crystallography; X-Ray; Drosophila; Drosophila; Endotoxins; Immunity; Innate; Nerve; Protein; Quaternary; Receptor; Nerve; Repetitive; Amino; Toll-Like Receptors

Subject Areas: Biology and Bio-materials

Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 25/09/2015 10:05

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