6WTS

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

Summary for 6WTS

• Entry DOI: 10.2210/pdb6wts/pdb
• EMDB information: 21898 21899
• Descriptor: SEMA6A, TcsL, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: cryoem, signaling protein-toxin complex, signaling protein/toxin
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 193188.73

Authors

Kucharska, I.,Rubinstein, J.L.,Julien, J.P. (deposition date: 2020-05-03, release date: 2020-07-08, Last modification date: 2024-10-09)

Primary citation

Lee, H.,Beilhartz, G.L.,Kucharska, I.,Raman, S.,Cui, H.,Lam, M.H.Y.,Liang, H.,Rubinstein, J.L.,Schramek, D.,Julien, J.P.,Melnyk, R.A.,Taipale, M.
Recognition of Semaphorin Proteins by P. sordellii Lethal Toxin Reveals Principles of Receptor Specificity in Clostridial Toxins.
Cell, 182:345-, 2020

PubMed Abstract: 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 Å 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.

PubMed: 32589945
DOI: 10.1016/j.cell.2020.06.005

Experimental method

ELECTRON MICROSCOPY (3.3 Å)