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| | ==IRS-1 PTB DOMAIN COMPLEXED WITH A IL-4 RECEPTOR PHOSPHOPEPTIDE, NMR, MINIMIZED AVERAGE STRUCTURE== | | ==IRS-1 PTB DOMAIN COMPLEXED WITH A IL-4 RECEPTOR PHOSPHOPEPTIDE, NMR, MINIMIZED AVERAGE STRUCTURE== |
| - | <StructureSection load='1irs' size='340' side='right'caption='[[1irs]], [[NMR_Ensembles_of_Models | 1 NMR models]]' scene=''> | + | <StructureSection load='1irs' size='340' side='right'caption='[[1irs]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1irs]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1IRS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1IRS FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1irs]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1IRS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1IRS FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 1 model</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PTB DOMAIN OF IRS-1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></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=1irs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1irs OCA], [https://pdbe.org/1irs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1irs RCSB], [https://www.ebi.ac.uk/pdbsum/1irs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1irs ProSAT]</span></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=1irs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1irs OCA], [https://pdbe.org/1irs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1irs RCSB], [https://www.ebi.ac.uk/pdbsum/1irs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1irs ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[https://www.uniprot.org/uniprot/IRS1_HUMAN IRS1_HUMAN]] Polymorphisms in IRS1 may be involved in the etiology of non-insulin-dependent diabetes mellitus (NIDDM) [MIM:[https://omim.org/entry/125853 125853]].<ref>PMID:14707024</ref> <ref>PMID:8723689</ref> <ref>PMID:10206679</ref> <ref>PMID:12843189</ref> <ref>PMID:15590636</ref>
| + | [https://www.uniprot.org/uniprot/IRS1_HUMAN IRS1_HUMAN] Polymorphisms in IRS1 may be involved in the etiology of non-insulin-dependent diabetes mellitus (NIDDM) [MIM:[https://omim.org/entry/125853 125853].<ref>PMID:14707024</ref> <ref>PMID:8723689</ref> <ref>PMID:10206679</ref> <ref>PMID:12843189</ref> <ref>PMID:15590636</ref> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/IRS1_HUMAN IRS1_HUMAN]] May mediate the control of various cellular processes by insulin. When phosphorylated by the insulin receptor binds specifically to various cellular proteins containing SH2 domains such as phosphatidylinositol 3-kinase p85 subunit or GRB2. Activates phosphatidylinositol 3-kinase when bound to the regulatory p85 subunit (By similarity).<ref>PMID:16878150</ref> <ref>PMID:14707024</ref> [[https://www.uniprot.org/uniprot/IL4RA_HUMAN IL4RA_HUMAN]] Receptor for both interleukin 4 and interleukin 13. Couples to the JAK1/2/3-STAT6 pathway. The IL4 response is involved in promoting Th2 differentiation. The IL4/IL13 responses are involved in regulating IgE production and, chemokine and mucus production at sites of allergic inflammation. In certain cell types, can signal through activation of insulin receptor substrates, IRS1/IRS2.<ref>PMID:8124718</ref> Soluble IL4R (sIL4R) inhibits IL4-mediated cell proliferation and IL5 up-regulation by T-cells.<ref>PMID:8124718</ref>
| + | [https://www.uniprot.org/uniprot/IRS1_HUMAN IRS1_HUMAN] May mediate the control of various cellular processes by insulin. When phosphorylated by the insulin receptor binds specifically to various cellular proteins containing SH2 domains such as phosphatidylinositol 3-kinase p85 subunit or GRB2. Activates phosphatidylinositol 3-kinase when bound to the regulatory p85 subunit (By similarity).<ref>PMID:16878150</ref> <ref>PMID:14707024</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | <jmolCheckbox> | | <jmolCheckbox> |
| | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ir/1irs_consurf.spt"</scriptWhenChecked> | | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ir/1irs_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: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Feisk, S W]] | + | [[Category: Feisk SW]] |
| - | [[Category: Huang, B]] | + | [[Category: Huang B]] |
| - | [[Category: Meadows, R P]] | + | [[Category: Meadows RP]] |
| - | [[Category: Miyazaki, M]] | + | [[Category: Miyazaki M]] |
| - | [[Category: Olejniczak, E T]] | + | [[Category: Olejniczak ET]] |
| - | [[Category: Shoelson, S E]] | + | [[Category: Shoelson SE]] |
| - | [[Category: Shuker, S B]] | + | [[Category: Shuker SB]] |
| - | [[Category: Trub, T]] | + | [[Category: Trub T]] |
| - | [[Category: Zhou, M M]] | + | [[Category: Zhou M-M]] |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Signal transduction]]
| + | |
| Structural highlights
Disease
IRS1_HUMAN Polymorphisms in IRS1 may be involved in the etiology of non-insulin-dependent diabetes mellitus (NIDDM) [MIM:125853.[1] [2] [3] [4] [5]
Function
IRS1_HUMAN May mediate the control of various cellular processes by insulin. When phosphorylated by the insulin receptor binds specifically to various cellular proteins containing SH2 domains such as phosphatidylinositol 3-kinase p85 subunit or GRB2. Activates phosphatidylinositol 3-kinase when bound to the regulatory p85 subunit (By similarity).[6] [7]
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
We present the NMR structure of the PTB domain of insulin receptor substrate-1 (IRS-1) complexed to a tyrosine-phosphorylated peptide derived from the IL-4 receptor. Despite the lack of sequence homology and different binding specificity, the overall fold of the protein is similar to that of the Shc PTB domain and closely resembles that of PH domains. However, the PTB domain of IRS-1 is smaller than that of Shc (110 versus 170 residues) and binds to phosphopeptides in a distinct manner. We explain the phosphopeptide binding specificity based on the structure of the complex and results of site-directed mutagenesis experiments.
Structural basis for IL-4 receptor phosphopeptide recognition by the IRS-1 PTB domain.,Zhou MM, Huang B, Olejniczak ET, Meadows RP, Shuker SB, Miyazaki M, Trub T, Shoelson SE, Fesik SW Nat Struct Biol. 1996 Apr;3(4):388-93. PMID:8599766[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Federici M, Pandolfi A, De Filippis EA, Pellegrini G, Menghini R, Lauro D, Cardellini M, Romano M, Sesti G, Lauro R, Consoli A. G972R IRS-1 variant impairs insulin regulation of endothelial nitric oxide synthase in cultured human endothelial cells. Circulation. 2004 Jan 27;109(3):399-405. Epub 2004 Jan 5. PMID:14707024 doi:10.1161/01.CIR.0000109498.77895.6F
- ↑ Esposito DL, Mammarella S, Ranieri A, Della Loggia F, Capani F, Consoli A, Mariani-Costantini R, Caramia FG, Cama A, Battista P. Deletion of Gly723 in the insulin receptor substrate-1 of a patient with noninsulin-dependent diabetes mellitus. Hum Mutat. 1996;7(4):364-6. PMID:8723689 doi:<364::AID-HUMU13>3.0.CO;2-0 10.1002/(SICI)1098-1004(1996)7:4<364::AID-HUMU13>3.0.CO;2-0
- ↑ Mammarella S, Creati B, Esposito DL, Arcuri P, Della Loggia F, Capani F, Mariani-Costantini R, Caramia FG, Battista P, Cama A. Novel allele of the insulin receptor substrate-1 bearing two non-conservative amino acid substitutions in a patient with noninsulin-dependent diabetes mellitus. Mutations in brief no. 130. Online. Hum Mutat. 1998;11(5):411. PMID:10206679 doi:<411::AID-HUMU11>3.0.CO;2-2 10.1002/(SICI)1098-1004(1998)11:5<411::AID-HUMU11>3.0.CO;2-2
- ↑ Marini MA, Frontoni S, Mineo D, Bracaglia D, Cardellini M, De Nicolais P, Baroni A, D'Alfonso R, Perna M, Lauro D, Federici M, Gambardella S, Lauro R, Sesti G. The Arg972 variant in insulin receptor substrate-1 is associated with an atherogenic profile in offspring of type 2 diabetic patients. J Clin Endocrinol Metab. 2003 Jul;88(7):3368-71. PMID:12843189
- ↑ McGettrick AJ, Feener EP, Kahn CR. Human insulin receptor substrate-1 (IRS-1) polymorphism G972R causes IRS-1 to associate with the insulin receptor and inhibit receptor autophosphorylation. J Biol Chem. 2005 Feb 25;280(8):6441-6. Epub 2004 Dec 7. PMID:15590636 doi:10.1074/jbc.M412300200
- ↑ Kuo AH, Stoica GE, Riegel AT, Wellstein A. Recruitment of insulin receptor substrate-1 and activation of NF-kappaB essential for midkine growth signaling through anaplastic lymphoma kinase. Oncogene. 2007 Feb 8;26(6):859-69. Epub 2006 Jul 31. PMID:16878150 doi:10.1038/sj.onc.1209840
- ↑ Federici M, Pandolfi A, De Filippis EA, Pellegrini G, Menghini R, Lauro D, Cardellini M, Romano M, Sesti G, Lauro R, Consoli A. G972R IRS-1 variant impairs insulin regulation of endothelial nitric oxide synthase in cultured human endothelial cells. Circulation. 2004 Jan 27;109(3):399-405. Epub 2004 Jan 5. PMID:14707024 doi:10.1161/01.CIR.0000109498.77895.6F
- ↑ Zhou MM, Huang B, Olejniczak ET, Meadows RP, Shuker SB, Miyazaki M, Trub T, Shoelson SE, Fesik SW. Structural basis for IL-4 receptor phosphopeptide recognition by the IRS-1 PTB domain. Nat Struct Biol. 1996 Apr;3(4):388-93. PMID:8599766
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