2f6e

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[[Image:2f6e.png|left|200px]]
 
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==Clostridium difficile Toxin A C-terminal fragment 1 (TcdA-f1)==
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The line below this paragraph, containing "STRUCTURE_2f6e", creates the "Structure Box" on the page.
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<StructureSection load='2f6e' size='340' side='right'caption='[[2f6e]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[2f6e]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Clostridioides_difficile Clostridioides difficile]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2F6E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2F6E FirstGlance]. <br>
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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]] 1.85&#8491;</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=2f6e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2f6e OCA], [https://pdbe.org/2f6e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2f6e RCSB], [https://www.ebi.ac.uk/pdbsum/2f6e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2f6e ProSAT]</span></td></tr>
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{{STRUCTURE_2f6e| PDB=2f6e | SCENE= }}
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</table>
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== Function ==
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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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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/f6/2f6e_consurf.spt"</scriptWhenChecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2f6e ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Clostridium difficile is a major nosocomial pathogen that produces two large protein toxins [toxin A (TcdA) and toxin B (TcdB)] capable of disrupting intestinal epithelial cells. Both belong to the family of large clostridial cytotoxins, which are characterized by the presence of a repetitive C-terminal repetitive domain (CRD). In TcdA, the CRD is composed of 39 repeats that are responsible for binding to cell surface carbohydrates. To understand the molecular structural basis of cell binding by the toxins from C. difficile, we have determined a 1.85-A resolution crystal structure of a 127-aa fragment from the C terminus of the toxin A CRD. This structure reveals a beta-solenoid fold containing five repeats, with each repeat consisting of a beta-hairpin followed by a loop of 7-10 residues in short repeats (SRs) or 18 residues in long repeats (LRs). Adjacent pairs of beta-hairpins are related to each other by either 90 degree or 120 degree screw-axis rotational relationships, depending on the nature of the amino acids at key positions in adjacent beta-hairpins. Models of the complete CRDs of toxins A and B suggest that each CRD contains straight stretches of beta-solenoid composed of three to five SRs that are punctuated by kinks introduced by the presence of a single LR. These structural features provide a framework for understanding how large clostridial cytotoxins bind to cell surfaces and suggest approaches for developing novel treatments for C. difficile-associated diseases by blocking the binding of toxins to cell surfaces.
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===Clostridium difficile Toxin A C-terminal fragment 1 (TcdA-f1)===
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Crystal structure of receptor-binding C-terminal repeats from Clostridium difficile toxin A.,Ho JG, Greco A, Rupnik M, Ng KK Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18373-8. Epub 2005 Dec 12. PMID:16344467<ref>PMID:16344467</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 class="pdbe-citations 2f6e" style="background-color:#fffaf0;"></div>
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(as it appears on PubMed at http://www.pubmed.gov), where 16344467 is the PubMed ID number.
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== References ==
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<references/>
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{{ABSTRACT_PUBMED_16344467}}
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__TOC__
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</StructureSection>
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==About this Structure==
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[[Category: Clostridioides difficile]]
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[[2f6e]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Clostridium_difficile Clostridium difficile]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2F6E OCA].
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[[Category: Large Structures]]
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[[Category: Ho JG]]
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==Reference==
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[[Category: Ng KK]]
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<ref group="xtra">PMID:016344467</ref><references group="xtra"/>
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[[Category: Clostridium difficile]]
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[[Category: Ho, J G.]]
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[[Category: Ng, K K.]]
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[[Category: Beta solenoid]]
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[[Category: C-terminal repetitive domain]]
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[[Category: Crop]]
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[[Category: Toxin]]
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Current revision

Clostridium difficile Toxin A C-terminal fragment 1 (TcdA-f1)

PDB ID 2f6e

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