3fzy

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[[Image:3fzy.png|left|200px]]
 
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{{STRUCTURE_3fzy| PDB=3fzy | SCENE= }}
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==Crystal Structure of Pre-cleavage Form of Cysteine Protease Domain from Vibrio cholerae RtxA Toxin==
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<StructureSection load='3fzy' size='340' side='right'caption='[[3fzy]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3fzy]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Vibrio_cholerae Vibrio cholerae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3FZY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3FZY 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]] 1.95&#8491;</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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=IHP:INOSITOL+HEXAKISPHOSPHATE'>IHP</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></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=3fzy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fzy OCA], [https://pdbe.org/3fzy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3fzy RCSB], [https://www.ebi.ac.uk/pdbsum/3fzy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3fzy ProSAT], [https://www.topsan.org/Proteins/CSGID/3fzy TOPSAN]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/MARTX_VIBCH MARTX_VIBCH] Precursor of a multifunctional toxin that causes destruction of the actin cytoskeleton by covalent cross-linking of actin and inactivation of Rho GTPases when translocated into the host cytoplasm (PubMed:26185092). Upon translocation into the host cell, undergoes autoprocessing in cis mediated by the peptidase C80 domain (also named CPD domain): the protease activity is activated upon binding inositol hexakisphosphate (InsP6) present at the host cell membrane and delivers the Cysteine protease domain-containing toxin F3 chain to the host cytosol (PubMed:17464284, PubMed:18591243, PubMed:18845756, PubMed:19620709, PubMed:19465933). The Cysteine protease domain-containing toxin F3 chain will then further cleave and release effector toxin chains that cause disassembly of the actin cytoskeleton and enhance V.cholerae colonization of the small intestine, possibly by facilitating evasion of phagocytic cells (PubMed:11553575, PubMed:12045243, PubMed:17698573, PubMed:17698571, PubMed:19812690, PubMed:19620709).<ref>PMID:11553575</ref> <ref>PMID:12045243</ref> <ref>PMID:17464284</ref> <ref>PMID:18591243</ref> <ref>PMID:18845756</ref> <ref>PMID:19465933</ref> <ref>PMID:19620709</ref> <ref>PMID:19812690</ref> <ref>PMID:26185092</ref> Following autocatalytic cleavage in cis at the Leu-3441-Ala-3442 site, this chain mediates processing in trans to release other individual toxin chains to the host cytosol (PubMed:19620709). Released effector toxin chains cause disassembly of the actin cytoskeleton and enhance V.cholerae colonization of the small intestine, possibly by facilitating evasion of phagocytic cells (PubMed:17698573, PubMed:17698571).<ref>PMID:17698571</ref> <ref>PMID:17698573</ref> <ref>PMID:19620709</ref> Actin-directed toxin that catalyzes the covalent cross-linking of host cytoplasmic monomeric actin (PubMed:11032799, PubMed:15199181, PubMed:16954226, PubMed:17951576, PubMed:19015515, PubMed:19656298, PubMed:23029200, PubMed:26228148). Mediates the cross-link between 'Lys-50' of one monomer and 'Glu-270' of another actin monomer, resulting in formation of highly toxic actin oligomers that cause cell rounding (PubMed:19015515). The toxin can be highly efficient at very low concentrations by acting on formin homology family proteins: toxic actin oligomers bind with high affinity to formins and adversely affect both nucleation and elongation abilities of formins, causing their potent inhibition in both profilin-dependent and independent manners (PubMed:26228148). Acts as an acid--amino-acid ligase that transfers the gamma-phosphoryl group of ATP to the 'Glu-270' actin residue, resulting in the formation of an activated acyl phosphate intermediate. This intermediate is further hydrolyzed and the energy of hydrolysis is utilized for the formation of the amide bond between actin subunits (PubMed:23029200).<ref>PMID:11032799</ref> <ref>PMID:15199181</ref> <ref>PMID:16954226</ref> <ref>PMID:17951576</ref> <ref>PMID:19015515</ref> <ref>PMID:19656298</ref> <ref>PMID:23029200</ref> <ref>PMID:26228148</ref> Actin-directed toxin that catalyzes the covalent cross-linking of host cytoplasmic monomeric actin (PubMed:11032799, PubMed:15199181, PubMed:16954226, PubMed:17951576, PubMed:19015515, PubMed:19656298, PubMed:23029200, PubMed:26228148). Mediates the cross-link between 'Lys-50' of one monomer and 'Glu-270' of another actin monomer, resulting in formation of highly toxic actin oligomers that cause cell rounding (PubMed:19015515). The toxin can be highly efficient at very low concentrations by acting on formin homology family proteins: toxic actin oligomers bind with high affinity to formins and adversely affect both nucleation and elongation abilities of formins, causing their potent inhibition in both profilin-dependent and independent manners (PubMed:26228148). Acts as an acid--amino-acid ligase that transfers the gamma-phosphoryl group of ATP to the 'Glu-270' actin residue, resulting in the formation of an activated acyl phosphate intermediate. This intermediate is further hydrolyzed and the energy of hydrolysis is utilized for the formation of the amide bond between actin subunits (PubMed:23029200).<ref>PMID:11032799</ref> <ref>PMID:15199181</ref> <ref>PMID:16954226</ref> <ref>PMID:17951576</ref> <ref>PMID:19015515</ref> <ref>PMID:19656298</ref> <ref>PMID:23029200</ref> <ref>PMID:26228148</ref> N-epsilon-fatty acyltransferase that mediates lysine-palmitoylation of host Rho GTPase proteins, with a strong preference for host Rac1 (PubMed:29074776). After delivery to the host cytosol, localizes to the host cell membrane where it palmitoylates host Rho GTPase proteins, resulting in loss of all active GTP-bound Rho and subsequent actin depolymerization (PubMed:17474905, PubMed:19434753, PubMed:23184949, PubMed:29074776). Prenylation of host Rac1 at the C-terminus is required for lysine-palmitoylation (PubMed:29074776).<ref>PMID:17474905</ref> <ref>PMID:19434753</ref> <ref>PMID:23184949</ref> <ref>PMID:29074776</ref> Indirectly activates the small GTPase CDC42.<ref>PMID:25427654</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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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fz/3fzy_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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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=3fzy 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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The multifunctional autoprocessing repeats-in-toxin (MARTX) toxin of Vibrio cholerae causes destruction of the actin cytoskeleton by covalent cross-linking of actin and inactivation of Rho GTPases. The effector domains responsible for these activities are here shown to be independent proteins released from the large toxin by autoproteolysis catalyzed by an embedded cysteine protease domain (CPD). The CPD is activated upon binding inositol hexakisphosphate (InsP(6)). In this study, we demonstrated that InsP(6) is not simply an allosteric cofactor, but rather binding of InsP(6) stabilized the CPD structure, facilitating formation of the enzyme-substrate complex. The 1.95-A crystal structure of this InsP(6)-bound unprocessed form of CPD was determined and revealed the scissile bond Leu(3428)-Ala(3429) captured in the catalytic site. Upon processing at this site, CPD was converted to a form with 500-fold reduced affinity for InsP(6), but was reactivated for high affinity binding of InsP(6) by cooperative binding of both a new substrate and InsP(6). Reactivation of CPD allowed cleavage of the MARTX toxin at other sites, specifically at leucine residues between the effector domains. Processed CPD also cleaved other proteins in trans, including the leucine-rich protein YopM, demonstrating that it is a promiscuous leucine-specific protease.
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===Crystal Structure of Pre-cleavage Form of Cysteine Protease Domain from Vibrio cholerae RtxA Toxin===
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Structural and molecular mechanism for autoprocessing of MARTX toxin of Vibrio cholerae at multiple sites.,Prochazkova K, Shuvalova LA, Minasov G, Voburka Z, Anderson WF, Satchell KJ J Biol Chem. 2009 Sep 25;284(39):26557-68. Epub 2009 Jul 20. PMID:19620709<ref>PMID:19620709</ref>
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{{ABSTRACT_PUBMED_19620709}}
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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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==About this Structure==
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<div class="pdbe-citations 3fzy" style="background-color:#fffaf0;"></div>
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[[3fzy]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Vibrio_cholerae Vibrio cholerae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3FZY OCA].
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== References ==
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<references/>
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==Reference==
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__TOC__
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<ref group="xtra">PMID:019620709</ref><references group="xtra"/>
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</StructureSection>
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[[Category: Large Structures]]
[[Category: Vibrio cholerae]]
[[Category: Vibrio cholerae]]
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[[Category: Anderson, W F.]]
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[[Category: Anderson WF]]
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[[Category: CSGID, Center for Structural Genomics of Infectious Diseases.]]
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[[Category: Minasov G]]
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[[Category: Minasov, G.]]
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[[Category: Prochazkova K]]
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[[Category: Prochazkova, K.]]
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[[Category: Satchell KJF]]
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[[Category: Satchell, K J.F.]]
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[[Category: Shuvalova L]]
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[[Category: Shuvalova, L.]]
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[[Category: Center for structural genomics of infectious disease]]
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[[Category: Cpd]]
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[[Category: Csgid]]
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[[Category: Cysteine protease domain]]
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[[Category: Idp00167]]
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[[Category: Pre-cleavage form]]
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[[Category: Rtxa toxin]]
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[[Category: Structural genomic]]
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[[Category: Toxin]]
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Current revision

Crystal Structure of Pre-cleavage Form of Cysteine Protease Domain from Vibrio cholerae RtxA Toxin

PDB ID 3fzy

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