| Structural highlights
Function
TCSL1_PAESO Precursor of a cytotoxin that targets the vascular endothelium, inducing an anti-inflammatory effect and resulting in lethal toxic shock syndrome (PubMed:19527792, PubMed:24919149, PubMed:29146177). TcsL constitutes the main toxin that mediates the pathology of P.sordellii infection, an anaerobic Gram-positive bacterium found in soil and in the gastrointestinal and vaginal tracts of animals and humans; although the majority of carriers are asymptomatic, pathogenic P.sordellii infections arise rapidly and are highly lethal (PubMed:29146177). This form constitutes the precursor of the toxin: it enters into host cells and mediates autoprocessing to release the active toxin (Glucosyltransferase TcsL) into the host cytosol (PubMed:32302524, PubMed:17334356, PubMed:27303685). Targets vascular endothelium by binding to the semaphorin proteins SEMA6A and SEMA6B, and enters host cells via clathrin-mediated endocytosis (PubMed:32302524). Once entered into host cells, acidification in the endosome promotes the membrane insertion of the translocation region and formation of a pore, leading to translocation of the GT44 and peptidase C80 domains across the endosomal membrane (By similarity). This activates the peptidase C80 domain and autocatalytic processing, releasing the N-terminal part (Glucosyltransferase TcsL), which constitutes the active part of the toxin, in the cytosol (PubMed:17334356, PubMed:27303685).[UniProtKB:P18177][1] [2] [3] [4] [5] [6] Active form of the toxin, which is released into the host cytosol following autoprocessing and inactivates small GTPases (PubMed:8626575, PubMed:8626586, PubMed:9632667, PubMed:17901056, PubMed:19744486, PubMed:24905543, PubMed:24919149, PubMed:27303685, PubMed:27023605, PubMed:30622517). Acts by mediating monoglucosylation of small GTPases of the Ras (H-Ras/HRAS, K-Ras/KRAS, N-Ras/NRAS and Ral/RALA) family in host cells at the conserved threonine residue located in the switch I region ('Thr-37/35'), using UDP-alpha-D-glucose as the sugar donor (PubMed:8858106, PubMed:8626575, PubMed:8626586, PubMed:9632667, PubMed:17901056, PubMed:19744486, PubMed:24905543, PubMed:24919149, PubMed:27023605, PubMed:30622517). Also able to catalyze monoglucosylation of some members of the Rho family (Rac1 and Rap2A), but with less efficiency than with Ras proteins (PubMed:8626586, PubMed:9632667, PubMed:19744486, PubMed:24905543). Monoglucosylation of host small GTPases completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form and leading to apoptosis (PubMed:8626586, PubMed:9632667, PubMed:17910886). Induces an anti-inflammatory effect, mainly by inactivating Ras proteins which results in blockage of the cell cycle and killing of immune cells (PubMed:17910886, PubMed:24919149). The absence or moderate local inflammatory response allows C.sordellii spreading in deep tissues, production of toxin which is released in the general circulation and causes a toxic shock syndrome (PubMed:24919149, PubMed:29146177).[7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Castanospermine was identified as an inhibitor of the Rho/Ras-glucosylating Clostridium sordellii lethal toxin and Clostridium difficile toxin B. Microinjection of castanospermine into embryonic bovine lung cells prevented the cytotoxic effects of toxins. The crystal structure of the glucosyltransferase domain of C. sordellii lethal toxin in complex with castanospermine, UDP and a calcium ion was solved at a resolution of 2.3A. The inhibitor binds in a conformation that brings its four hydroxyl groups and its N-atom almost exactly in the positions of the four hydroxyls and of the ring oxygen of the glucosyl moiety of UDP-glucose, respectively.
Inhibition of the glucosyltransferase activity of clostridial Rho/Ras-glucosylating toxins by castanospermine.,Jank T, Ziegler MO, Schulz GE, Aktories K FEBS Lett. 2008 Jun 25;582(15):2277-82. Epub 2008 May 27. PMID:18505687[20]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Reineke J, Tenzer S, Rupnik M, Koschinski A, Hasselmayer O, Schrattenholz A, Schild H, von Eichel-Streiber C. Autocatalytic cleavage of Clostridium difficile toxin B. Nature. 2007 Mar 22;446(7134):415-9. doi: 10.1038/nature05622. Epub 2007 Mar 4. PMID:17334356 doi:http://dx.doi.org/10.1038/nature05622
- ↑ Hao Y, Senn T, Opp JS, Young VB, Thiele T, Srinivas G, Huang SK, Aronoff DM. Lethal toxin is a critical determinant of rapid mortality in rodent models of Clostridium sordellii endometritis. Anaerobe. 2010 Apr;16(2):155-60. PMID:19527792 doi:10.1016/j.anaerobe.2009.06.002
- ↑ Xu H, Yang J, Gao W, Li L, Li P, Zhang L, Gong YN, Peng X, Xi JJ, Chen S, Wang F, Shao F. Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. Nature. 2014 Sep 11;513(7517):237-41. doi: 10.1038/nature13449. Epub 2014 Jun 11. PMID:24919149 doi:http://dx.doi.org/10.1038/nature13449
- ↑ Craven R, Lacy DB. Clostridium sordellii Lethal-Toxin Autoprocessing and Membrane Localization Activities Drive GTPase Glucosylation Profiles in Endothelial Cells. mSphere. 2015 Nov 18;1(1):e00012-15. PMID:27303685 doi:10.1128/mSphere.00012-15
- ↑ Tian S, Liu Y, Wu H, Liu H, Zeng J, Choi MY, Chen H, Gerhard R, Dong M. Genome-Wide CRISPR Screen Identifies Semaphorin 6A and 6B as Receptors for Paeniclostridium sordellii Toxin TcsL. Cell Host Microbe. 2020 May 13;27(5):782-792.e7. PMID:32302524 doi:10.1016/j.chom.2020.03.007
- ↑ Popoff MR. Clostridium difficile and Clostridium sordellii toxins, proinflammatory versus anti-inflammatory response. Toxicon. 2018 Jul;149:54-64. PMID:29146177 doi:10.1016/j.toxicon.2017.11.003
- ↑ Jank T, Giesemann T, Aktories K. Clostridium difficile glucosyltransferase toxin B-essential amino acids for substrate binding. J Biol Chem. 2007 Nov 30;282(48):35222-31. doi: 10.1074/jbc.M703138200. Epub 2007 , Sep 27. PMID:17901056 doi:http://dx.doi.org/10.1074/jbc.M703138200
- ↑ Voth DE, Ballard JD. Critical intermediate steps in Clostridium sordellii lethal toxin-induced apoptosis. Biochem Biophys Res Commun. 2007 Nov 30;363(4):959-64. PMID:17910886 doi:10.1016/j.bbrc.2007.09.073
- ↑ Huelsenbeck SC, Klose I, Reichenbach M, Huelsenbeck J, Genth H. Distinct kinetics of (H/K/N)Ras glucosylation and Rac1 glucosylation catalysed by Clostridium sordellii lethal toxin. FEBS Lett. 2009 Oct 6;583(19):3133-9. PMID:19744486 doi:10.1016/j.febslet.2009.09.006
- ↑ Genth H, Pauillac S, Schelle I, Bouvet P, Bouchier C, Varela-Chavez C, Just I, Popoff MR. Haemorrhagic toxin and lethal toxin from Clostridium sordellii strain vpi9048: molecular characterization and comparative analysis of substrate specificity of the large clostridial glucosylating toxins. Cell Microbiol. 2014 Nov;16(11):1706-21. doi: 10.1111/cmi.12321. Epub 2014 Aug 4. PMID:24905543 doi:http://dx.doi.org/10.1111/cmi.12321
- ↑ Xu H, Yang J, Gao W, Li L, Li P, Zhang L, Gong YN, Peng X, Xi JJ, Chen S, Wang F, Shao F. Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. Nature. 2014 Sep 11;513(7517):237-41. doi: 10.1038/nature13449. Epub 2014 Jun 11. PMID:24919149 doi:http://dx.doi.org/10.1038/nature13449
- ↑ Varela Chavez C, Haustant GM, Baron B, England P, Chenal A, Pauillac S, Blondel A, Popoff MR. The Tip of the Four N-Terminal α-Helices of Clostridium sordellii Lethal Toxin Contains the Interaction Site with Membrane Phosphatidylserine Facilitating Small GTPases Glucosylation. Toxins (Basel). 2016 Mar 25;8(4):90. PMID:27023605 doi:10.3390/toxins8040090
- ↑ Craven R, Lacy DB. Clostridium sordellii Lethal-Toxin Autoprocessing and Membrane Localization Activities Drive GTPase Glucosylation Profiles in Endothelial Cells. mSphere. 2015 Nov 18;1(1):e00012-15. PMID:27303685 doi:10.1128/mSphere.00012-15
- ↑ Genth H, Junemann J, Lammerhirt CM, Lucke AC, Schelle I, Just I, Gerhard R, Pich A. Difference in Mono-O-Glucosylation of Ras Subtype GTPases Between Toxin A and Toxin B From Clostridioides difficile Strain 10463 and Lethal Toxin From Clostridium sordellii Strain 6018. Front Microbiol. 2018 Dec 21;9:3078. doi: 10.3389/fmicb.2018.03078. eCollection, 2018. PMID:30622517 doi:http://dx.doi.org/10.3389/fmicb.2018.03078
- ↑ Just I, Selzer J, Hofmann F, Green GA, Aktories K. Inactivation of Ras by Clostridium sordellii lethal toxin-catalyzed glucosylation. J Biol Chem. 1996 Apr 26;271(17):10149-53. PMID:8626575 doi:10.1074/jbc.271.17.10149
- ↑ Popoff MR, Chaves-Olarte E, Lemichez E, von Eichel-Streiber C, Thelestam M, Chardin P, Cussac D, Antonny B, Chavrier P, Flatau G, Giry M, de Gunzburg J, Boquet P. Ras, Rap, and Rac small GTP-binding proteins are targets for Clostridium sordellii lethal toxin glucosylation. J Biol Chem. 1996 Apr 26;271(17):10217-24. PMID:8626586 doi:10.1074/jbc.271.17.10217
- ↑ Hofmann F, Rex G, Aktories K, Just I. The ras-related protein Ral is monoglucosylated by Clostridium sordellii lethal toxin. Biochem Biophys Res Commun. 1996 Oct 3;227(1):77-81. PMID:8858106 doi:10.1006/bbrc.1996.1470
- ↑ Herrmann C, Ahmadian MR, Hofmann F, Just I. Functional consequences of monoglucosylation of Ha-Ras at effector domain amino acid threonine 35. J Biol Chem. 1998 Jun 26;273(26):16134-9. PMID:9632667 doi:10.1074/jbc.273.26.16134
- ↑ Popoff MR. Clostridium difficile and Clostridium sordellii toxins, proinflammatory versus anti-inflammatory response. Toxicon. 2018 Jul;149:54-64. PMID:29146177 doi:10.1016/j.toxicon.2017.11.003
- ↑ Jank T, Ziegler MO, Schulz GE, Aktories K. Inhibition of the glucosyltransferase activity of clostridial Rho/Ras-glucosylating toxins by castanospermine. FEBS Lett. 2008 Jun 25;582(15):2277-82. Epub 2008 May 27. PMID:18505687 doi:10.1016/j.febslet.2008.05.025
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