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| - | {{Seed}} | |
| - | [[Image:3ahq.jpg|left|200px]] | |
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| - | <!-- | + | ==hyperactive human Ero1== |
| - | The line below this paragraph, containing "STRUCTURE_3ahq", creates the "Structure Box" on the page.
| + | <StructureSection load='3ahq' size='340' side='right'caption='[[3ahq]], [[Resolution|resolution]] 2.35Å' scene=''> |
| - | You may change the PDB parameter (which sets the PDB file loaded into the applet)
| + | == Structural highlights == |
| - | or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
| + | <table><tr><td colspan='2'>[[3ahq]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3AHQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3AHQ FirstGlance]. <br> |
| - | or leave the SCENE parameter empty for the default display.
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.35Å</td></tr> |
| - | --> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene></td></tr> |
| - | {{STRUCTURE_3ahq| PDB=3ahq | SCENE= }}
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3ahq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ahq OCA], [https://pdbe.org/3ahq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ahq RCSB], [https://www.ebi.ac.uk/pdbsum/3ahq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ahq ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/ERO1A_HUMAN ERO1A_HUMAN] Oxidoreductase involved in disulfide bond formation in the endoplasmic reticulum. Efficiently reoxidizes P4HB/PDI, the enzyme catalyzing protein disulfide formation, in order to allow P4HB to sustain additional rounds of disulfide formation. Following P4HB reoxidation, passes its electrons to molecular oxygen via FAD, leading to the production of reactive oxygen species (ROS) in the cell. Required for the proper folding of immunoglobulins. Involved in the release of the unfolded cholera toxin from reduced P4HB/PDI in case of infection by V.cholerae, thereby playing a role in retrotranslocation of the toxin. Plays an important role in ER stress-induced, CHOP-dependent apoptosis by activating the inositol 1,4,5-trisphosphate receptor IP3R1.<ref>PMID:10671517</ref> <ref>PMID:10970843</ref> <ref>PMID:11707400</ref> <ref>PMID:12403808</ref> <ref>PMID:18833192</ref> <ref>PMID:18971943</ref> <ref>PMID:23027870</ref> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | In the endoplasmic reticulum (ER) of eukaryotic cells, Ero1 flavoenzymes promote oxidative protein folding through protein disulphide isomerase (PDI), generating reactive oxygen species (hydrogen peroxide) as byproducts. Therefore, Ero1 activity must be strictly regulated to avoid futile oxidation cycles in the ER. Although regulatory mechanisms restraining Ero1alpha activity ensure that not all PDIs are oxidized, its specificity towards PDI could allow other resident oxidoreductases to remain reduced and competent to carry out isomerization and reduction of protein substrates. In this study, crystal structures of human Ero1alpha were solved in its hyperactive and inactive forms. Our findings reveal that human Ero1alpha modulates its oxidative activity by properly positioning regulatory cysteines within an intrinsically flexible loop, and by fine-tuning the electron shuttle ability of the loop through disulphide rearrangements. Specific PDI targeting is guaranteed by electrostatic and hydrophobic interactions of Ero1alpha with the PDI b'-domain through its substrate-binding pocket. These results reveal the molecular basis of the regulation and specificity of protein disulphide formation in human cells. |
| | | | |
| - | ===hyperactive human Ero1===
| + | Crystal structures of human Ero1alpha reveal the mechanisms of regulated and targeted oxidation of PDI.,Inaba K, Masui S, Iida H, Vavassori S, Sitia R, Suzuki M EMBO J. 2010 Oct 6;29(19):3330-43. Epub 2010 Sep 10. PMID:20834232<ref>PMID:20834232</ref> |
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| - | | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | <!--
| + | </div> |
| - | The line below this paragraph, {{ABSTRACT_PUBMED_20834232}}, adds the Publication Abstract to the page
| + | <div class="pdbe-citations 3ahq" style="background-color:#fffaf0;"></div> |
| - | (as it appears on PubMed at http://www.pubmed.gov), where 20834232 is the PubMed ID number.
| + | == References == |
| - | -->
| + | <references/> |
| - | {{ABSTRACT_PUBMED_20834232}}
| + | __TOC__ |
| - | | + | </StructureSection> |
| - | ==About this Structure== | + | |
| - | 3AHQ is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3AHQ OCA].
| + | |
| - | | + | |
| - | ==Reference== | + | |
| - | <ref group="xtra">PMID:20834232</ref><references group="xtra"/> | + | |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Inaba, K.]] | + | [[Category: Large Structures]] |
| - | [[Category: Sitia, R.]] | + | [[Category: Inaba K]] |
| - | [[Category: Suzuki, M.]] | + | [[Category: Sitia R]] |
| - | [[Category: Disulfide bond]] | + | [[Category: Suzuki M]] |
| - | [[Category: Hyperactive human ero1]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Pdi]]
| + | |
| - | [[Category: Redox]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Dec 22 09:51:47 2010''
| + | |
| Structural highlights
Function
ERO1A_HUMAN Oxidoreductase involved in disulfide bond formation in the endoplasmic reticulum. Efficiently reoxidizes P4HB/PDI, the enzyme catalyzing protein disulfide formation, in order to allow P4HB to sustain additional rounds of disulfide formation. Following P4HB reoxidation, passes its electrons to molecular oxygen via FAD, leading to the production of reactive oxygen species (ROS) in the cell. Required for the proper folding of immunoglobulins. Involved in the release of the unfolded cholera toxin from reduced P4HB/PDI in case of infection by V.cholerae, thereby playing a role in retrotranslocation of the toxin. Plays an important role in ER stress-induced, CHOP-dependent apoptosis by activating the inositol 1,4,5-trisphosphate receptor IP3R1.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
In the endoplasmic reticulum (ER) of eukaryotic cells, Ero1 flavoenzymes promote oxidative protein folding through protein disulphide isomerase (PDI), generating reactive oxygen species (hydrogen peroxide) as byproducts. Therefore, Ero1 activity must be strictly regulated to avoid futile oxidation cycles in the ER. Although regulatory mechanisms restraining Ero1alpha activity ensure that not all PDIs are oxidized, its specificity towards PDI could allow other resident oxidoreductases to remain reduced and competent to carry out isomerization and reduction of protein substrates. In this study, crystal structures of human Ero1alpha were solved in its hyperactive and inactive forms. Our findings reveal that human Ero1alpha modulates its oxidative activity by properly positioning regulatory cysteines within an intrinsically flexible loop, and by fine-tuning the electron shuttle ability of the loop through disulphide rearrangements. Specific PDI targeting is guaranteed by electrostatic and hydrophobic interactions of Ero1alpha with the PDI b'-domain through its substrate-binding pocket. These results reveal the molecular basis of the regulation and specificity of protein disulphide formation in human cells.
Crystal structures of human Ero1alpha reveal the mechanisms of regulated and targeted oxidation of PDI.,Inaba K, Masui S, Iida H, Vavassori S, Sitia R, Suzuki M EMBO J. 2010 Oct 6;29(19):3330-43. Epub 2010 Sep 10. PMID:20834232[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Cabibbo A, Pagani M, Fabbri M, Rocchi M, Farmery MR, Bulleid NJ, Sitia R. ERO1-L, a human protein that favors disulfide bond formation in the endoplasmic reticulum. J Biol Chem. 2000 Feb 18;275(7):4827-33. PMID:10671517
- ↑ Benham AM, Cabibbo A, Fassio A, Bulleid N, Sitia R, Braakman I. The CXXCXXC motif determines the folding, structure and stability of human Ero1-Lalpha. EMBO J. 2000 Sep 1;19(17):4493-502. PMID:10970843 doi:http://dx.doi.org/10.1093/emboj/19.17.4493
- ↑ Mezghrani A, Fassio A, Benham A, Simmen T, Braakman I, Sitia R. Manipulation of oxidative protein folding and PDI redox state in mammalian cells. EMBO J. 2001 Nov 15;20(22):6288-96. PMID:11707400 doi:http://dx.doi.org/10.1093/emboj/20.22.6288
- ↑ Tsai B, Rapoport TA. Unfolded cholera toxin is transferred to the ER membrane and released from protein disulfide isomerase upon oxidation by Ero1. J Cell Biol. 2002 Oct 28;159(2):207-16. Epub 2002 Oct 28. PMID:12403808 doi:http://dx.doi.org/10.1083/jcb.200207120
- ↑ Appenzeller-Herzog C, Riemer J, Christensen B, Sorensen ES, Ellgaard L. A novel disulphide switch mechanism in Ero1alpha balances ER oxidation in human cells. EMBO J. 2008 Nov 19;27(22):2977-87. doi: 10.1038/emboj.2008.202. Epub 2008 Oct 2. PMID:18833192 doi:http://dx.doi.org/10.1038/emboj.2008.202
- ↑ Baker KM, Chakravarthi S, Langton KP, Sheppard AM, Lu H, Bulleid NJ. Low reduction potential of Ero1alpha regulatory disulphides ensures tight control of substrate oxidation. EMBO J. 2008 Nov 19;27(22):2988-97. doi: 10.1038/emboj.2008.230. Epub 2008 Oct, 30. PMID:18971943 doi:http://dx.doi.org/10.1038/emboj.2008.230
- ↑ Hansen HG, Schmidt JD, Soltoft CL, Ramming T, Geertz-Hansen HM, Christensen B, Sorensen ES, Juncker AS, Appenzeller-Herzog C, Ellgaard L. Hyperactivity of the Ero1alpha oxidase elicits endoplasmic reticulum stress but no broad antioxidant response. J Biol Chem. 2012 Nov 16;287(47):39513-23. doi: 10.1074/jbc.M112.405050. Epub, 2012 Oct 1. PMID:23027870 doi:http://dx.doi.org/10.1074/jbc.M112.405050
- ↑ Inaba K, Masui S, Iida H, Vavassori S, Sitia R, Suzuki M. Crystal structures of human Ero1alpha reveal the mechanisms of regulated and targeted oxidation of PDI. EMBO J. 2010 Oct 6;29(19):3330-43. Epub 2010 Sep 10. PMID:20834232 doi:10.1038/emboj.2010.222
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