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| | <StructureSection load='5sxp' size='340' side='right'caption='[[5sxp]], [[Resolution|resolution]] 1.65Å' scene=''> | | <StructureSection load='5sxp' size='340' side='right'caption='[[5sxp]], [[Resolution|resolution]] 1.65Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5sxp]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5SXP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5SXP FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5sxp]] is a 6 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=5SXP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5SXP FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ARHGEF7, COOL1, KIAA0142, P85SPR, PAK3BP, PIXB, Nbla10314 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), ITCH ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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]] 1.65Å</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=5sxp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5sxp OCA], [http://pdbe.org/5sxp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5sxp RCSB], [http://www.ebi.ac.uk/pdbsum/5sxp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5sxp 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=5sxp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5sxp OCA], [https://pdbe.org/5sxp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5sxp RCSB], [https://www.ebi.ac.uk/pdbsum/5sxp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5sxp ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[http://www.uniprot.org/uniprot/ITCH_HUMAN ITCH_HUMAN]] Defects in ITCH are the cause of syndromic multisystem autoimmune disease (SMAD) [MIM:[http://omim.org/entry/613385 613385]]. SMAD is characterized by organomegaly, failure to thrive, developmental delay, dysmorphic features and autoimmune inflammatory cell infiltration of the lungs, liver and gut.<ref>PMID:20170897</ref> | |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ARHG7_HUMAN ARHG7_HUMAN]] Acts as a RAC1 guanine nucleotide exchange factor (GEF) and can induce membrane ruffling. Functions in cell migration, attachment and cell spreading. Promotes targeting of RAC1 to focal adhesions (By similarity). May function as a positive regulator of apoptosis. Downstream of NMDA receptors and CaMKK-CaMK1 signaling cascade, promotes the formation of spines and synapses in hippocampal neurons.<ref>PMID:19041750</ref> <ref>PMID:18716323</ref> <ref>PMID:18184567</ref> [[http://www.uniprot.org/uniprot/ITCH_HUMAN ITCH_HUMAN]] Acts as an E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. It catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation. It is involved in the control of inflammatory signaling pathways. Is an essential component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 and RNF11, that ensures the transient nature of inflammatory signaling pathways. Promotes the association of the complex after TNF stimulation. Once the complex is formed, TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains. This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NFKB1. Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2-dependent signal transduction pathways. Regulates the transcriptional activity of several transcription factors, and probably plays an important role in the regulation of immune response. Ubiquitinates NFE2 by 'Lys-63' linkages and is implicated in the control of the development of hematopoietic lineages. Critical regulator of T-helper (TH2) cytokine development through its ability to induce JUNB ubiquitination and degradation (By similarity). Ubiquitinates SNX9. Ubiquitinates CXCR4 and HGS/HRS and regulates sorting of CXCR4 to the degradative pathway. It is involved in the negative regulation of MAVS-dependent cellular antiviral responses. Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation. Involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP. Mediates the antiapoptotic activity of epidermal growth factor through the ubiquitination and proteasomal degradation of p15 BID. Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination.<ref>PMID:14602072</ref> <ref>PMID:17028573</ref> <ref>PMID:16387660</ref> <ref>PMID:18718448</ref> <ref>PMID:18718449</ref> <ref>PMID:18628966</ref> <ref>PMID:19592251</ref> <ref>PMID:19131965</ref> <ref>PMID:19881509</ref> <ref>PMID:20392206</ref> <ref>PMID:20068034</ref> | + | [https://www.uniprot.org/uniprot/ARHG7_HUMAN ARHG7_HUMAN] Acts as a RAC1 guanine nucleotide exchange factor (GEF) and can induce membrane ruffling. Functions in cell migration, attachment and cell spreading. Promotes targeting of RAC1 to focal adhesions (By similarity). May function as a positive regulator of apoptosis. Downstream of NMDA receptors and CaMKK-CaMK1 signaling cascade, promotes the formation of spines and synapses in hippocampal neurons.<ref>PMID:19041750</ref> <ref>PMID:18716323</ref> <ref>PMID:18184567</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5sxp" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5sxp" style="background-color:#fffaf0;"></div> |
| - | | |
| - | ==See Also== | |
| - | *[[Rho guanine nucleotide exchange factor 3D structures|Rho guanine nucleotide exchange factor 3D structures]] | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Angers, A]] | + | [[Category: Angers A]] |
| - | [[Category: Cappadocia, L]] | + | [[Category: Cappadocia L]] |
| - | [[Category: Desrochers, G]] | + | [[Category: Desrochers G]] |
| - | [[Category: Lussier-Price, M]] | + | [[Category: Lussier-Price M]] |
| - | [[Category: Omichinski, J G]] | + | [[Category: Omichinski JG]] |
| - | [[Category: Ligase]]
| + | |
| - | [[Category: Sh3 domain peptide ligand complex]]
| + | |
| - | [[Category: Signaling protein-ligase complex]]
| + | |
| Structural highlights
Function
ARHG7_HUMAN Acts as a RAC1 guanine nucleotide exchange factor (GEF) and can induce membrane ruffling. Functions in cell migration, attachment and cell spreading. Promotes targeting of RAC1 to focal adhesions (By similarity). May function as a positive regulator of apoptosis. Downstream of NMDA receptors and CaMKK-CaMK1 signaling cascade, promotes the formation of spines and synapses in hippocampal neurons.[1] [2] [3]
Publication Abstract from PubMed
The ligase Itch plays major roles in signalling pathways by inducing ubiquitylation-dependent degradation of several substrates. Substrate recognition and binding is critical for the regulation of this reaction. Like closely related ligases, Itch can interact with proteins containing a PPxY motif via its WW domains. In addition to these WW domains, Itch possesses a proline-rich region (PRR) that has been shown to interact with several Src Homology 3 (SH3) domain-containing proteins. We have previously established that despite the apparent surface uniformity and conserved fold of SH3 domains, they display different binding mechanisms and affinities for their interaction with the PRR of Itch. Here, we attempt to determine the molecular bases underlying the wide range of binding properties of the Itch PRR. Using pull-down assays combined with mass spectrometry analysis, we show that the Itch PRR preferentially forms complexes with Endophilins, Amphyphisins and Pacsins, but can also target a variety of other SH3 domain-containing proteins. In addition, we map the binding sites of these proteins using a combination of PRR sub-sequences and mutants. We find that different SH3 domains target distinct proline-rich sequences overlapping significantly. We also structurally analyze these protein complexes using crystallography and molecular modelling. These structures depict the position of Itch PRR engaged in a 1:2 protein complex with beta-PIX and a 1:1 complex with the other SH3 domain-containing proteins. Taken together, these results reveal the binding preferences of the Itch PRR towards its most common SH3 domain-containing partners, and demonstrate that the PRR region is sufficient for binding.
Molecular Basis of Interactions Between SH3 Domain-Containing Proteins and the Proline-Rich Region of the Ubiquitin Ligase Itch.,Desrochers G, Cappadocia L, Lussier-Price M, Ton AT, Ayoubi R, Serohijos A, Omichinski JG, Angers A J Biol Chem. 2017 Feb 24. pii: jbc.M116.754440. doi: 10.1074/jbc.M116.754440. PMID:28235806[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zhan L, Rosenberg A, Bergami KC, Yu M, Xuan Z, Jaffe AB, Allred C, Muthuswamy SK. Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma. Cell. 2008 Nov 28;135(5):865-78. doi: 10.1016/j.cell.2008.09.045. PMID:19041750 doi:10.1016/j.cell.2008.09.045
- ↑ Nola S, Sebbagh M, Marchetto S, Osmani N, Nourry C, Audebert S, Navarro C, Rachel R, Montcouquiol M, Sans N, Etienne-Manneville S, Borg JP, Santoni MJ. Scrib regulates PAK activity during the cell migration process. Hum Mol Genet. 2008 Nov 15;17(22):3552-65. doi: 10.1093/hmg/ddn248. Epub 2008 Aug, 20. PMID:18716323 doi:10.1093/hmg/ddn248
- ↑ Saneyoshi T, Wayman G, Fortin D, Davare M, Hoshi N, Nozaki N, Natsume T, Soderling TR. Activity-dependent synaptogenesis: regulation by a CaM-kinase kinase/CaM-kinase I/betaPIX signaling complex. Neuron. 2008 Jan 10;57(1):94-107. doi: 10.1016/j.neuron.2007.11.016. PMID:18184567 doi:http://dx.doi.org/10.1016/j.neuron.2007.11.016
- ↑ Desrochers G, Cappadocia L, Lussier-Price M, Ton AT, Ayoubi R, Serohijos A, Omichinski JG, Angers A. Molecular Basis of Interactions Between SH3 Domain-Containing Proteins and the Proline-Rich Region of the Ubiquitin Ligase Itch. J Biol Chem. 2017 Feb 24. pii: jbc.M116.754440. doi: 10.1074/jbc.M116.754440. PMID:28235806 doi:http://dx.doi.org/10.1074/jbc.M116.754440
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