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| - | [[Image:1z2m.gif|left|200px]]<br /> | |
| - | <applet load="1z2m" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1z2m, resolution 2.50Å" /> | |
| - | '''Crystal Structure of ISG15, the Interferon-Induced Ubiquitin Cross Reactive Protein'''<br /> | |
| | | | |
| - | ==Overview== | + | ==Crystal Structure of ISG15, the Interferon-Induced Ubiquitin Cross Reactive Protein== |
| - | The biological effects of the ISG15 protein arise in part from its, conjugation to cellular targets as a primary response to, interferon-alpha/beta induction and other markers of viral or parasitic, infection. Recombinant full-length ISG15 has been produced for the first, time in high yield by mutating Cys78 to stabilize the protein and by, cloning in a C-terminal arginine cap to protect the C terminus against, proteolytic inactivation. The cap is subsequently removed with, carboxypeptidase B to yield mature biologically active ISG15 capable of, stoichiometric ATP-dependent thiolester formation with its human UbE1L, activating enzyme. The three-dimensional structure of recombinant, ISG15C78S was determined at 2.4-A resolution. The ISG15 structure, comprises two beta-grasp folds having main chain root mean square, deviation (r.m.s.d.) values from ubiquitin of 1.7 A (N-terminal) and 1.0 A, (C-terminal). The beta-grasp domains pack across two conserved 3(10), helices to bury 627 A2 that accounts for 7% of the total, solvent-accessible surface area. The distribution of ISG15 surface charge, forms a ridge of negative charge extending nearly the full-length of the, molecule. Additionally, the N-terminal domain contains an apolar region, comprising almost half its solvent accessible surface. The C-terminal, domain of ISG15 was superimposed on the structure of Nedd8 (r.m.s.d. =, 0.84 A) bound to its AppBp1-Uba3 activating enzyme to model ISG15 binding, to UbE1L. The docking model predicts several key side-chain interactions, that presumably define the specificity between the ubiquitin and ISG15, ligation pathways to maintain functional integrity of their signaling.
| + | <StructureSection load='1z2m' size='340' side='right'caption='[[1z2m]], [[Resolution|resolution]] 2.50Å' scene=''> |
| - | | + | == Structural highlights == |
| - | ==About this Structure== | + | <table><tr><td colspan='2'>[[1z2m]] 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=1Z2M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1Z2M FirstGlance]. <br> |
| - | 1Z2M is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with OS4 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1Z2M OCA].
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5Å</td></tr> |
| - | | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OS4:OSMIUM+4++ION'>OS4</scene></td></tr> |
| - | ==Reference== | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1z2m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1z2m OCA], [https://pdbe.org/1z2m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1z2m RCSB], [https://www.ebi.ac.uk/pdbsum/1z2m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1z2m ProSAT]</span></td></tr> |
| - | Crystal structure of the interferon-induced ubiquitin-like protein ISG15., Narasimhan J, Wang M, Fu Z, Klein JM, Haas AL, Kim JJ, J Biol Chem. 2005 Jul 22;280(29):27356-65. Epub 2005 May 24. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15917233 15917233]
| + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/ISG15_HUMAN ISG15_HUMAN] Ubiquitin-like protein that is conjugated to intracellular target proteins after IFN-alpha or IFN-beta stimulation. Its enzymatic pathway is partially distinct from that of ubiquitin, differing in substrate specificity and interaction with ligating enzymes. ISG15 conjugation pathway uses a dedicated E1 enzyme, but seems to converge with the Ub conjugation pathway at the level of a specific E2 enzyme. Targets include STAT1, SERPINA3G/SPI2A, JAK1, MAPK3/ERK1, PLCG1, EIF2AK2/PKR, MX1/MxA, and RIG-1. Deconjugated by USP18/UBP43. Shows specific chemotactic activity towards neutrophils and activates them to induce release of eosinophil chemotactic factors. May serve as a trans-acting binding factor directing the association of ligated target proteins to intermediate filaments. May also be involved in autocrine, paracrine and endocrine mechanisms, as in cell-to-cell signaling, possibly partly by inducing IFN-gamma secretion by monocytes and macrophages. Seems to display antiviral activity during viral infections.<ref>PMID:1373138</ref> <ref>PMID:7526157</ref> <ref>PMID:8550581</ref> <ref>PMID:2005397</ref> <ref>PMID:16254333</ref> <ref>PMID:16009940</ref> In response to IFN-tau secreted by the conceptus, may ligate to and regulate proteins involved in the release of prostaglandin F2-alpha (PGF), and thus prevent lysis of the corpus luteum and maintain the pregnancy (By similarity).<ref>PMID:1373138</ref> <ref>PMID:7526157</ref> <ref>PMID:8550581</ref> <ref>PMID:2005397</ref> <ref>PMID:16254333</ref> <ref>PMID:16009940</ref> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/z2/1z2m_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </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=1z2m ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Single protein]] | + | [[Category: Large Structures]] |
| - | [[Category: Fu, Z.]] | + | [[Category: Fu Z]] |
| - | [[Category: Haas, A.L.]] | + | [[Category: Haas AL]] |
| - | [[Category: Kim, J.J.]] | + | [[Category: Kim JJ]] |
| - | [[Category: Klein, J.M.]] | + | [[Category: Klein JM]] |
| - | [[Category: Narasimhan, J.]] | + | [[Category: Narasimhan J]] |
| - | [[Category: Wang, M.]] | + | [[Category: Wang M]] |
| - | [[Category: OS4]]
| + | |
| - | [[Category: isg15]]
| + | |
| - | [[Category: ubiquitin cross reactive protein]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 20:28:36 2007''
| + | |
| Structural highlights
Function
ISG15_HUMAN Ubiquitin-like protein that is conjugated to intracellular target proteins after IFN-alpha or IFN-beta stimulation. Its enzymatic pathway is partially distinct from that of ubiquitin, differing in substrate specificity and interaction with ligating enzymes. ISG15 conjugation pathway uses a dedicated E1 enzyme, but seems to converge with the Ub conjugation pathway at the level of a specific E2 enzyme. Targets include STAT1, SERPINA3G/SPI2A, JAK1, MAPK3/ERK1, PLCG1, EIF2AK2/PKR, MX1/MxA, and RIG-1. Deconjugated by USP18/UBP43. Shows specific chemotactic activity towards neutrophils and activates them to induce release of eosinophil chemotactic factors. May serve as a trans-acting binding factor directing the association of ligated target proteins to intermediate filaments. May also be involved in autocrine, paracrine and endocrine mechanisms, as in cell-to-cell signaling, possibly partly by inducing IFN-gamma secretion by monocytes and macrophages. Seems to display antiviral activity during viral infections.[1] [2] [3] [4] [5] [6] In response to IFN-tau secreted by the conceptus, may ligate to and regulate proteins involved in the release of prostaglandin F2-alpha (PGF), and thus prevent lysis of the corpus luteum and maintain the pregnancy (By similarity).[7] [8] [9] [10] [11] [12]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
References
- ↑ Loeb KR, Haas AL. The interferon-inducible 15-kDa ubiquitin homolog conjugates to intracellular proteins. J Biol Chem. 1992 Apr 15;267(11):7806-13. PMID:1373138
- ↑ Loeb KR, Haas AL. Conjugates of ubiquitin cross-reactive protein distribute in a cytoskeletal pattern. Mol Cell Biol. 1994 Dec;14(12):8408-19. PMID:7526157
- ↑ Narasimhan J, Potter JL, Haas AL. Conjugation of the 15-kDa interferon-induced ubiquitin homolog is distinct from that of ubiquitin. J Biol Chem. 1996 Jan 5;271(1):324-30. PMID:8550581
- ↑ Knight E Jr, Cordova B. IFN-induced 15-kDa protein is released from human lymphocytes and monocytes. J Immunol. 1991 Apr 1;146(7):2280-4. PMID:2005397
- ↑ Lenschow DJ, Giannakopoulos NV, Gunn LJ, Johnston C, O'Guin AK, Schmidt RE, Levine B, Virgin HW 4th. Identification of interferon-stimulated gene 15 as an antiviral molecule during Sindbis virus infection in vivo. J Virol. 2005 Nov;79(22):13974-83. PMID:16254333 doi:79/22/13974
- ↑ Zhao C, Denison C, Huibregtse JM, Gygi S, Krug RM. Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10200-5. Epub 2005 Jul 11. PMID:16009940 doi:0504754102
- ↑ Loeb KR, Haas AL. The interferon-inducible 15-kDa ubiquitin homolog conjugates to intracellular proteins. J Biol Chem. 1992 Apr 15;267(11):7806-13. PMID:1373138
- ↑ Loeb KR, Haas AL. Conjugates of ubiquitin cross-reactive protein distribute in a cytoskeletal pattern. Mol Cell Biol. 1994 Dec;14(12):8408-19. PMID:7526157
- ↑ Narasimhan J, Potter JL, Haas AL. Conjugation of the 15-kDa interferon-induced ubiquitin homolog is distinct from that of ubiquitin. J Biol Chem. 1996 Jan 5;271(1):324-30. PMID:8550581
- ↑ Knight E Jr, Cordova B. IFN-induced 15-kDa protein is released from human lymphocytes and monocytes. J Immunol. 1991 Apr 1;146(7):2280-4. PMID:2005397
- ↑ Lenschow DJ, Giannakopoulos NV, Gunn LJ, Johnston C, O'Guin AK, Schmidt RE, Levine B, Virgin HW 4th. Identification of interferon-stimulated gene 15 as an antiviral molecule during Sindbis virus infection in vivo. J Virol. 2005 Nov;79(22):13974-83. PMID:16254333 doi:79/22/13974
- ↑ Zhao C, Denison C, Huibregtse JM, Gygi S, Krug RM. Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10200-5. Epub 2005 Jul 11. PMID:16009940 doi:0504754102
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