title: Structural insight into the mechanism of activation of the Toll receptor by the dimeric ligand Spätzle.
abstract: The Drosophila Toll receptor, which functions in both embryonic patterning and innate immunity to fungi and Gram-positive bacteria, is activated by a dimeric cytokine ligand, Spätzle (Spz). Previous studies have suggested that one Spz cross-links two Toll receptor molecules to form an activated complex. Here we report electron microscopy structures of the Toll ectodomain in the absence and presence of Spz. Contrary to expectations, Spz does not directly cross-link two Toll ectodomains. Instead, Spz binding at the N-terminal end of Toll predominantly induces the formation of a 2:2 complex, with two sites of interaction between the ectodomain chains, one located near to the N terminus of the solenoid and the other between the C-terminal juxtamembrane sequences. Moreover, Toll undergoes a ligand-induced conformational change, becoming more tightly curved than in the apo form. The unexpected 2:2 complex was confirmed by mass spectrometry under native conditions. These results suggest that activation of Toll is an allosteric mechanism induced by an end-on binding mode of its ligand Spz.
authors.affiliation: Department of Biochemistry, Cambridge University, Cambridge, UK.
authors.forename: Monique
authors.initials: M
authors.lastname: Gangloff
authors.forename: Ayaluru
authors.initials: A
authors.lastname: Murali
authors.forename: Jin
authors.initials: J
authors.lastname: Xiong
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Arnot
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Weber
authors.forename: Alan M
authors.initials: AM
authors.lastname: Sandercock
authors.forename: Carol V
authors.initials: CV
authors.lastname: Robinson
authors.forename: Robert
authors.initials: R
authors.lastname: Sarisky
authors.forename: Andreas
authors.initials: A
authors.lastname: Holzenburg
authors.forename: Cheng
authors.initials: C
authors.lastname: Kao
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Gay
mesh_terms: D000818:Animals; D002460:Cell Line; D020285:Cryoelectron Microscopy; D019281:Dimerization; D029721:Drosophila Proteins / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D004331:Drosophila melanogaster / Q000378:metabolism; D008024:Ligands; D011485:Protein Binding; D018411:Spodoptera; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D008024:Ligands; C068721:Tl protein, Drosophila; D051193:Toll-Like Receptors; C086179:spz protein, Drosophila