2lty

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==NEDD4L WW2 domain in complex with a Smad7 derived peptide==
==NEDD4L WW2 domain in complex with a Smad7 derived peptide==
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<StructureSection load='2lty' size='340' side='right' caption='[[2lty]], [[NMR_Ensembles_of_Models | 30 NMR models]]' scene=''>
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<StructureSection load='2lty' size='340' side='right'caption='[[2lty]]' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[2lty]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2LTY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2LTY FirstGlance]. <br>
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<table><tr><td colspan='2'>[[2lty]] 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=2LTY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2LTY FirstGlance]. <br>
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</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2ltv|2ltv]], [[2ltw|2ltw]], [[2ltx|2ltx]], [[2ltz|2ltz]]</td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NEDD4L, KIAA0439, NEDL3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2lty FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2lty OCA], [https://pdbe.org/2lty PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2lty RCSB], [https://www.ebi.ac.uk/pdbsum/2lty PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2lty ProSAT]</span></td></tr>
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<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=2lty FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2lty OCA], [http://pdbe.org/2lty PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2lty RCSB], [http://www.ebi.ac.uk/pdbsum/2lty PDBsum]</span></td></tr>
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</table>
</table>
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== Disease ==
 
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[[http://www.uniprot.org/uniprot/SMAD7_HUMAN SMAD7_HUMAN]] Genetic variations in SMAD7 influence susceptibility to colorectal cancer type 3 (CRCS3) [MIM:[http://omim.org/entry/612229 612229]]. Colorectal cancer consists of tumors or cancer of either the colon or rectum or both. Cancers of the large intestine are the second most common form of cancer found in males and females. Symptoms include rectal bleeding, occult blood in stools, bowel obstruction and weight loss. Treatment is based largely on the extent of cancer penetration into the intestinal wall. Surgical cures are possible if the malignancy is confined to the intestine. Risk can be reduced when following a diet which is low in fat and high in fiber.<ref>PMID:17934461</ref>
 
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/NED4L_HUMAN NED4L_HUMAN]] 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. Inhibits TGF-beta signaling by triggering SMAD2 and TGFBR1 ubiquitination and proteasome-dependent degradation. Promotes ubiquitination and internalization of various plasma membrane channels such as ENaC, Nav1.2, Nav1.3, Nav1.5, Nav1.7, Nav1.8, Kv1.3, EAAT1 or CLC5. Promotes ubiquitination and degradation of SGK1 and TNK2.<ref>PMID:12911626</ref> <ref>PMID:15217910</ref> <ref>PMID:15489223</ref> <ref>PMID:15040001</ref> <ref>PMID:15496141</ref> <ref>PMID:15576372</ref> <ref>PMID:19144635</ref> [[http://www.uniprot.org/uniprot/SMAD7_HUMAN SMAD7_HUMAN]] Antagonist of signaling by TGF-beta (transforming growth factor) type 1 receptor superfamily members; has been shown to inhibit TGF-beta (Transforming growth factor) and activin signaling by associating with their receptors thus preventing SMAD2 access. Functions as an adapter to recruit SMURF2 to the TGF-beta receptor complex. Also acts by recruiting the PPP1R15A-PP1 complex to TGFBR1, which promotes its dephosphorylation. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator (By similarity).<ref>PMID:9892009</ref> <ref>PMID:11163210</ref> <ref>PMID:12023024</ref> <ref>PMID:14718519</ref> <ref>PMID:17327236</ref>
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[https://www.uniprot.org/uniprot/NED4L_HUMAN NED4L_HUMAN] 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. Inhibits TGF-beta signaling by triggering SMAD2 and TGFBR1 ubiquitination and proteasome-dependent degradation. Promotes ubiquitination and internalization of various plasma membrane channels such as ENaC, Nav1.2, Nav1.3, Nav1.5, Nav1.7, Nav1.8, Kv1.3, EAAT1 or CLC5. Promotes ubiquitination and degradation of SGK1 and TNK2.<ref>PMID:12911626</ref> <ref>PMID:15217910</ref> <ref>PMID:15489223</ref> <ref>PMID:15040001</ref> <ref>PMID:15496141</ref> <ref>PMID:15576372</ref> <ref>PMID:19144635</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Transforming growth factor (TGF)-beta and BMP signaling is mediated by Smads 1-5 (R-Smads and Co-Smads) and inhibited by Smad7, a major hub of regulation of TGF-beta and BMP receptors by negative feedback and antagonistic signals. The transcription coactivator YAP and the E3 ubiquitin ligases Smurf1/2 and Nedd4L target R-Smads for activation or degradation, respectively. Pairs of WW domain in these regulators bind PY motifs and adjacent CDK/MAPK and GSK3 phosphorylation sites in R-Smads in a selective and regulated manner. In contrast, here we show that Smad7 binds YAP, Smurf1, Smurf2, and Nedd4L constitutively, the binding involving a PY motif in Smad7 and no phosphorylation. We also provide a structural basis for how regulators that use WW domain pairs for selective interactions with R-Smads, resort to one single versatile WW domain for binding Smad7 to centralize regulation in the TGF-beta and BMP pathways.
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Structural Basis for the Versatile Interactions of Smad7 with Regulator WW Domains in TGF-beta Pathways.,Aragon E, Goerner N, Xi Q, Gomes T, Gao S, Massague J, Macias MJ Structure. 2012 Oct 10;20(10):1726-36. doi: 10.1016/j.str.2012.07.014. Epub 2012 , Aug 23. PMID:22921829<ref>PMID:22921829</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 2lty" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Ubiquitin protein ligase|Ubiquitin protein ligase]]
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*[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Aragon, E]]
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[[Category: Large Structures]]
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[[Category: Gao, S]]
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[[Category: Aragon E]]
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[[Category: Goerner, N]]
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[[Category: Gao S]]
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[[Category: Lopes, T]]
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[[Category: Goerner N]]
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[[Category: Macias, M J]]
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[[Category: Lopes T]]
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[[Category: Massague, J]]
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[[Category: Macias MJ]]
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[[Category: Xi, Q]]
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[[Category: Massague J]]
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[[Category: Nedd4l]]
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[[Category: Xi Q]]
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[[Category: Protein binding-peptide complex]]
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[[Category: Smad7]]
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[[Category: Ww]]
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Current revision

NEDD4L WW2 domain in complex with a Smad7 derived peptide

PDB ID 2lty

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