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| | <StructureSection load='3vrp' size='340' side='right'caption='[[3vrp]], [[Resolution|resolution]] 1.52Å' scene=''> | | <StructureSection load='3vrp' size='340' side='right'caption='[[3vrp]], [[Resolution|resolution]] 1.52Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3vrp]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3VRP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3VRP FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3vrp]] is a 2 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=3VRP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3VRP FirstGlance]. <br> |
| - | </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></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]] 1.52Å</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>
| + | <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=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3vrn|3vrn]], [[3vro|3vro]], [[3vrq|3vrq]], [[3vrr|3vrr]]</div></td></tr> | + | |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CBLC ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </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=3vrp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3vrp OCA], [https://pdbe.org/3vrp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3vrp RCSB], [https://www.ebi.ac.uk/pdbsum/3vrp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3vrp 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=3vrp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3vrp OCA], [https://pdbe.org/3vrp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3vrp RCSB], [https://www.ebi.ac.uk/pdbsum/3vrp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3vrp ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[https://www.uniprot.org/uniprot/EGFR_HUMAN EGFR_HUMAN]] Defects in EGFR are associated with lung cancer (LNCR) [MIM:[https://omim.org/entry/211980 211980]]. LNCR is a common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. | |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/CBLC_HUMAN CBLC_HUMAN]] Regulator of EGFR mediated signal transduction. [[https://www.uniprot.org/uniprot/EGFR_HUMAN EGFR_HUMAN]] Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TGFA/TGF-alpha, amphiregulin, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules. May also activate the NF-kappa-B signaling cascade. Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling. Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin.<ref>PMID:7657591</ref> <ref>PMID:11602604</ref> <ref>PMID:12873986</ref> <ref>PMID:10805725</ref> <ref>PMID:11116146</ref> <ref>PMID:11483589</ref> <ref>PMID:17115032</ref> <ref>PMID:21258366</ref> <ref>PMID:12297050</ref> <ref>PMID:12620237</ref> <ref>PMID:15374980</ref> <ref>PMID:19560417</ref> <ref>PMID:20837704</ref> Isoform 2 may act as an antagonist of EGF action.<ref>PMID:7657591</ref> <ref>PMID:11602604</ref> <ref>PMID:12873986</ref> <ref>PMID:10805725</ref> <ref>PMID:11116146</ref> <ref>PMID:11483589</ref> <ref>PMID:17115032</ref> <ref>PMID:21258366</ref> <ref>PMID:12297050</ref> <ref>PMID:12620237</ref> <ref>PMID:15374980</ref> <ref>PMID:19560417</ref> <ref>PMID:20837704</ref>
| + | [https://www.uniprot.org/uniprot/CBLC_HUMAN CBLC_HUMAN] Regulator of EGFR mediated signal transduction. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Receptor protein-tyrosine kinase]]
| + | [[Category: Isozaki Y]] |
| - | [[Category: Isozaki, Y]] | + | [[Category: Nakagawa A]] |
| - | [[Category: Nakagawa, A]] | + | [[Category: Suzuki M]] |
| - | [[Category: Suzuki, M]] | + | [[Category: Takeshita K]] |
| - | [[Category: Takeshita, K]] | + | [[Category: Tezuka T]] |
| - | [[Category: Tezuka, T]] | + | [[Category: Yamamoto T]] |
| - | [[Category: Yamamoto, T]] | + | [[Category: Yamanashi Y]] |
| - | [[Category: Yamanashi, Y]] | + | [[Category: Yamashita E]] |
| - | [[Category: Yamashita, E]] | + | |
| - | [[Category: Calcium-binding ef hand]]
| + | |
| - | [[Category: Divergent sh2 domain]]
| + | |
| - | [[Category: Protein binding-transferase complex]]
| + | |
| - | [[Category: Ptb domain]]
| + | |
| - | [[Category: Regulator of egfr mediated signal transduction]]
| + | |
| - | [[Category: Ubiquitously expressed]]
| + | |
| Structural highlights
Function
CBLC_HUMAN Regulator of EGFR mediated signal transduction.
Publication Abstract from PubMed
Through their ubiquitin ligase activity, Cbl-family proteins suppress signalling mediated by protein-tyrosine kinases (PTKs), but can also function as adaptor proteins to positively regulate signalling. The tyrosine kinase binding (TKB) domain of this family is critical for binding with tyrosine-phosphorylated target proteins. Here, we analysed the crystal structure of the TKB domain of Cbl-c/Cbl-3 (Cbl-c TKB), which is a distinct member of the mammalian Cbl-family. In comparison with Cbl TKB, Cbl-c TKB showed restricted structural flexibility upon phosphopeptide binding. A mutation in Cbl-c TKB augmenting this flexibility enhanced its binding to target phosphoproteins. These results suggest that proteins, post-translational modifications or mutations that alter structural flexibility of the TKB domain of Cbl-family proteins could regulate their binding to target phosphoproteins and thereby, affect PTK-mediated signalling.
Structural flexibility regulates phosphopeptide-binding activity of the tyrosine kinase binding domain of Cbl-c.,Takeshita K, Tezuka T, Isozaki Y, Yamashita E, Suzuki M, Kim M, Yamanashi Y, Yamamoto T, Nakagawa A J Biochem. 2012 Nov;152(5):487-95. doi: 10.1093/jb/mvs085. Epub 2012 Aug 9. PMID:22888118[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Takeshita K, Tezuka T, Isozaki Y, Yamashita E, Suzuki M, Kim M, Yamanashi Y, Yamamoto T, Nakagawa A. Structural flexibility regulates phosphopeptide-binding activity of the tyrosine kinase binding domain of Cbl-c. J Biochem. 2012 Nov;152(5):487-95. doi: 10.1093/jb/mvs085. Epub 2012 Aug 9. PMID:22888118 doi:http://dx.doi.org/10.1093/jb/mvs085
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