6wts | pdb_00006wts

CryoEM structure of the C. sordellii lethal toxin TcsL in complex with SEMA6A

spinqualitylabelsall models 6wts, resolution 3.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6wts is a 3 chain structure with sequence from "bacillus_oedematis_sporogenes"_sordelli_1923 "bacillus oedematis sporogenes" sordelli 1923 and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: NAG Gene: SEMA6A, KIAA1368, SEMAQ (HUMAN), tcsL, JGS6382_PCS1300041 ("Bacillus oedematis sporogenes" Sordelli 1923) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [SEM6A_HUMAN] Cell surface receptor for PLXNA2 that plays an important role in cell-cell signaling. Required for normal granule cell migration in the developing cerebellum. Promotes reorganization of the actin cytoskeleton and plays an important role in axon guidance in the developing central nervous system. Can act as repulsive axon guidance cue. Has repulsive action towards migrating granular neurons. May play a role in channeling sympathetic axons into the sympathetic chains and controlling the temporal sequence of sympathetic target innervation (By similarity). Publication Abstract from PubMed Pathogenic clostridial species secrete potent toxins that induce severe host tissue damage. Paeniclostridium sordellii lethal toxin (TcsL) causes an almost invariably lethal toxic shock syndrome associated with gynecological infections. TcsL is 87% similar to C. difficile TcdB, which enters host cells via Frizzled receptors in colon epithelium. However, P. sordellii infections target vascular endothelium, suggesting that TcsL exploits another receptor. Here, using CRISPR/Cas9 screening, we establish semaphorins SEMA6A and SEMA6B as TcsL receptors. We demonstrate that recombinant SEMA6A can protect mice from TcsL-induced edema. A 3.3 A cryo-EM structure shows that TcsL binds SEMA6A with the same region that in TcdB binds structurally unrelated Frizzled. Remarkably, 15 mutations in this evolutionarily divergent surface are sufficient to switch binding specificity of TcsL to that of TcdB. Our findings establish semaphorins as physiologically relevant receptors for TcsL and reveal the molecular basis for the difference in tissue targeting and disease pathogenesis between highly related toxins. Recognition of Semaphorin Proteins by P. sordellii Lethal Toxin Reveals Principles of Receptor Specificity in Clostridial Toxins.,Lee H, Beilhartz GL, Kucharska I, Raman S, Cui H, Lam MHY, Liang H, Rubinstein JL, Schramek D, Julien JP, Melnyk RA, Taipale M Cell. 2020 Jun 23. pii: S0092-8674(20)30692-9. doi: 10.1016/j.cell.2020.06.005. PMID:32589945 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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