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| | ==CRYSTAL STRUCTURE OF THE OLIGOMERIZATION DOMAIN FROM ROTAVIRUS NSP4== | | ==CRYSTAL STRUCTURE OF THE OLIGOMERIZATION DOMAIN FROM ROTAVIRUS NSP4== |
| - | <StructureSection load='1g1i' size='340' side='right' caption='[[1g1i]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='1g1i' size='340' side='right'caption='[[1g1i]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1g1i]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1G1I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1G1I FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1g1i]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Simian_rotavirus_A/SA11 Simian rotavirus A/SA11]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1G1I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1G1I FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1g1j|1g1j]]</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=1g1i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1g1i OCA], [https://pdbe.org/1g1i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1g1i RCSB], [https://www.ebi.ac.uk/pdbsum/1g1i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1g1i ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1g1i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1g1i OCA], [http://pdbe.org/1g1i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1g1i RCSB], [http://www.ebi.ac.uk/pdbsum/1g1i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1g1i ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/NSP4_ROTS1 NSP4_ROTS1] Plays an essential role in the virus replication cycle by acting as a viroporin. Creates a pore in the host reticulum endoplasmic and as a consequence releases Ca(2+) in the cytoplasm of infected cell. In turn, high levels of cytoplasmic calcium trigger membrane trafficking and transport of viral ER-associated proteins to viroplasms, sites of viral genome replication and immature particle assembly.[HAMAP-Rule:MF_04091]<ref>PMID:21151776</ref> <ref>PMID:7637021</ref> <ref>PMID:9108087</ref> The secreted form acts as an enterotoxin that causes phospholipase C-dependent elevation of the intracellular calcium concentration in host intestinal mucosa cells. Increased concentration of intracellular calcium disrupts the cytoskeleton and the tight junctions, raising the paracellular permeability. Potentiates chloride ion secretion through a calcium ion-dependent signaling pathway, inducing age-dependent diarrhea. To perform this enterotoxigenic role in vivo, NSP4 is released from infected enterocytes in a soluble form capable of diffusing within the intestinal lumen and interacting with host plasma membrane receptors on neighboring epithelial cells such as integrins ITGA1/ITGB1 and ITGA2/ITGB1.[HAMAP-Rule:MF_04091]<ref>PMID:17035333</ref> <ref>PMID:18587047</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/g1/1g1i_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/g1/1g1i_consurf.spt"</scriptWhenChecked> |
| - | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Bowman, G D]] | + | [[Category: Large Structures]] |
| - | [[Category: Nodelman, I M]] | + | [[Category: Simian rotavirus A/SA11]] |
| - | [[Category: Schutt, C E]] | + | [[Category: Bowman GD]] |
| - | [[Category: Homo-tetramer]] | + | [[Category: Nodelman IM]] |
| - | [[Category: Metal binding protein]] | + | [[Category: Schutt CE]] |
| - | [[Category: Metal binding site]]
| + | |
| - | [[Category: Ns28]]
| + | |
| - | [[Category: Parallel coiled-coil]]
| + | |
| Structural highlights
Function
NSP4_ROTS1 Plays an essential role in the virus replication cycle by acting as a viroporin. Creates a pore in the host reticulum endoplasmic and as a consequence releases Ca(2+) in the cytoplasm of infected cell. In turn, high levels of cytoplasmic calcium trigger membrane trafficking and transport of viral ER-associated proteins to viroplasms, sites of viral genome replication and immature particle assembly.[HAMAP-Rule:MF_04091][1] [2] [3] The secreted form acts as an enterotoxin that causes phospholipase C-dependent elevation of the intracellular calcium concentration in host intestinal mucosa cells. Increased concentration of intracellular calcium disrupts the cytoskeleton and the tight junctions, raising the paracellular permeability. Potentiates chloride ion secretion through a calcium ion-dependent signaling pathway, inducing age-dependent diarrhea. To perform this enterotoxigenic role in vivo, NSP4 is released from infected enterocytes in a soluble form capable of diffusing within the intestinal lumen and interacting with host plasma membrane receptors on neighboring epithelial cells such as integrins ITGA1/ITGB1 and ITGA2/ITGB1.[HAMAP-Rule:MF_04091][4] [5]
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
During the maturation of rotaviral particles, non-structural protein 4 (NSP4) plays a critical role in the translocation of the immature capsid into the lumen of the endoplasmic reticulum. Full-length NSP4 and a 22 amino acid peptide (NSP4(114-135)) derived from this protein have been shown to induce diarrhea in young mice in an age-dependent manner, and may therefore be the agent responsible for rotavirally-induced symptoms. We have determined the crystal structure of the oligomerization domain of NSP4 which spans residues 95 to 137 (NSP4(95-137)). NSP4(95-137) self-associates into a parallel, tetrameric coiled-coil, with the hydrophobic core interrupted by three polar layers occupying a and d-heptad positions. Side-chains from two consecutive polar layers, consisting of four Gln123 and two of the four Glu120 residues, coordinate a divalent cation. Two independent structures built from MAD-phased data indicated the presence of a strontium and calcium ion bound at this site, respectively. This metal-binding site appears to play an important role in stabilizing the homo-tetramer, which has implications for the engagement of NSP4 as an enterotoxin.
Crystal structure of the oligomerization domain of NSP4 from rotavirus reveals a core metal-binding site.,Bowman GD, Nodelman IM, Levy O, Lin SL, Tian P, Zamb TJ, Udem SA, Venkataraghavan B, Schutt CE J Mol Biol. 2000 Dec 15;304(5):861-71. PMID:11124032[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hyser JM, Collinson-Pautz MR, Utama B, Estes MK. Rotavirus disrupts calcium homeostasis by NSP4 viroporin activity. mBio. 2010 Nov 30;1(5):e00265-10. PMID:21151776 doi:10.1128/mBio.00265-10
- ↑ Tian P, Estes MK, Hu Y, Ball JM, Zeng CQ, Schilling WP. The rotavirus nonstructural glycoprotein NSP4 mobilizes Ca2+ from the endoplasmic reticulum. J Virol. 1995 Sep;69(9):5763-72. PMID:7637021 doi:10.1128/JVI.69.9.5763-5772.1995
- ↑ Dong Y, Zeng CQ, Ball JM, Estes MK, Morris AP. The rotavirus enterotoxin NSP4 mobilizes intracellular calcium in human intestinal cells by stimulating phospholipase C-mediated inositol 1,4,5-trisphosphate production. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3960-5. PMID:9108087 doi:10.1073/pnas.94.8.3960
- ↑ Bugarcic A, Taylor JA. Rotavirus nonstructural glycoprotein NSP4 is secreted from the apical surfaces of polarized epithelial cells. J Virol. 2006 Dec;80(24):12343-9. PMID:17035333 doi:10.1128/JVI.01378-06
- ↑ Seo NS, Zeng CQ, Hyser JM, Utama B, Crawford SE, Kim KJ, Höök M, Estes MK. Integrins alpha1beta1 and alpha2beta1 are receptors for the rotavirus enterotoxin. Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):8811-8. PMID:18587047 doi:10.1073/pnas.0803934105
- ↑ Bowman GD, Nodelman IM, Levy O, Lin SL, Tian P, Zamb TJ, Udem SA, Venkataraghavan B, Schutt CE. Crystal structure of the oligomerization domain of NSP4 from rotavirus reveals a core metal-binding site. J Mol Biol. 2000 Dec 15;304(5):861-71. PMID:11124032 doi:10.1006/jmbi.2000.4250
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