3ss1

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<StructureSection load='3ss1' size='340' side='right'caption='[[3ss1]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
<StructureSection load='3ss1' size='340' side='right'caption='[[3ss1]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3ss1]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Clod6 Clod6]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SS1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SS1 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3ss1]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Clostridioides_difficile_630 Clostridioides difficile 630]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SS1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SS1 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.202&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3srz|3srz]]</div></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CD0663, CD630_06630, tcdA ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=272563 CLOD6])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3ss1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ss1 OCA], [https://pdbe.org/3ss1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ss1 RCSB], [https://www.ebi.ac.uk/pdbsum/3ss1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ss1 ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3ss1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ss1 OCA], [https://pdbe.org/3ss1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ss1 RCSB], [https://www.ebi.ac.uk/pdbsum/3ss1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ss1 ProSAT]</span></td></tr>
</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/TCDA_CLODI TCDA_CLODI] Precursor of a cytotoxin that targets and disrupts the colonic epithelium, inducing the host inflammatory and innate immune responses and resulting in diarrhea and pseudomembranous colitis (PubMed:20844489). TcdA and TcdB constitute the main toxins that mediate the pathology of C.difficile infection, an opportunistic pathogen that colonizes the colon when the normal gut microbiome is disrupted (PubMed:19252482, PubMed:20844489). Compared to TcdB, TcdA is less virulent and less important for inducing the host inflammatory and innate immune responses (PubMed:19252482). This form constitutes the precursor of the toxin: it enters into host cells and mediates autoprocessing to release the active toxin (Glucosyltransferase TcdA) into the host cytosol (By similarity). Targets colonic epithelia by binding to some receptor, and enters host cells via clathrin-mediated endocytosis (By similarity). Binding to LDLR, as well as carbohydrates and sulfated glycosaminoglycans on host cell surface contribute to entry into cells (PubMed:1670930, PubMed:31160825, PubMed:16622409). In contrast to TcdB, Frizzled receptors FZD1, FZD2 and FZD7 do not act as host receptors in the colonic epithelium for TcdA (PubMed:27680706). 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 TcdA), which constitutes the active part of the toxin, in the cytosol (PubMed:17334356, PubMed:19553670, PubMed:27571750).[UniProtKB:P18177]<ref>PMID:16622409</ref> <ref>PMID:1670930</ref> <ref>PMID:17334356</ref> <ref>PMID:19252482</ref> <ref>PMID:19553670</ref> <ref>PMID:20844489</ref> <ref>PMID:27571750</ref> <ref>PMID:27680706</ref> <ref>PMID:31160825</ref> Active form of the toxin, which is released into the host cytosol following autoprocessing and inactivates small GTPases (PubMed:7775453, PubMed:24905543, PubMed:30622517, PubMed:22747490, PubMed:22267739). Acts by mediating monoglucosylation of small GTPases of the Rho family (Rac1, RhoA, RhoB, RhoC, Rap2A and Cdc42) 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:7775453, PubMed:24905543, PubMed:30622517, PubMed:22747490, PubMed:22267739). Monoglucosylation of host small GTPases completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption and cell death, resulting in the loss of colonic epithelial barrier function (PubMed:7775453). Also able to catalyze monoglucosylation of some members of the Ras family (H-Ras/HRAS, K-Ras/KRAS and N-Ras/NRAS), but with much less efficiency than with Rho proteins, suggesting that it does not act on Ras proteins in vivo (PubMed:30622517).<ref>PMID:22267739</ref> <ref>PMID:22747490</ref> <ref>PMID:24905543</ref> <ref>PMID:30622517</ref> <ref>PMID:7775453</ref>
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The principle virulence factors in Clostridium difficile pathogenesis are TcdA and TcdB, homologous glucosyltransferases capable of inactivating small GTPases within the host cell. We present crystal structures of the TcdA glucosyltransferase domain (GTD) in the presence and absence of the co-substrate UDP-glucose. While the enzymatic core is similar to that of TcdB, the proposed GTPase-binding surface differs significantly. We show that TcdA is comparable to TcdB in its modification of Rho-family substrates and that, unlike TcdB, TcdA is also capable of modifying Rap-family GTPases both in vitro and in cells. The glucosyltransferase activities of both toxins are reduced in the context of the holotoxin but can be restored with autoproteolytic activation and GTD release. These studies highlight the importance of cellular activation in determining the array of substrates available to the toxins once delivered into the cell.
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Structural determinants of the Clostridium difficile toxin A glucosyltransferase activity.,Pruitt RN, Chumbler NM, Rutherford SA, Farrow MA, Friedman DB, Spiller B, Lacy DB J Biol Chem. 2012 Jan 20. PMID:22267739<ref>PMID:22267739</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 3ss1" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Clod6]]
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[[Category: Clostridioides difficile 630]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Chumbler, N M]]
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[[Category: Chumbler NM]]
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[[Category: Farrow, M A]]
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[[Category: Farrow MA]]
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[[Category: Friedman, D B]]
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[[Category: Friedman DB]]
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[[Category: Lacy, D B]]
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[[Category: Lacy DB]]
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[[Category: Pruitt, R N]]
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[[Category: Pruitt RN]]
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[[Category: Seeback, S A]]
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[[Category: Seeback SA]]
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[[Category: Spiller, B W]]
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[[Category: Spiller BW]]
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[[Category: Glucosyltransferase]]
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[[Category: Transferase]]
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Current revision

Clostridium difficile toxin A (TcdA) glucolsyltransferase domain

PDB ID 3ss1

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OCA

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