View source for 2laj


==Third WW domain of human Nedd4L in complex with doubly phosphorylated human smad3 derived peptide==
<StructureSection load='2laj' size='340' side='right'caption='[[2laj]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2laj]] 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=2LAJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2LAJ FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 15 models</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</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=2laj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2laj OCA], [https://pdbe.org/2laj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2laj RCSB], [https://www.ebi.ac.uk/pdbsum/2laj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2laj ProSAT]</span></td></tr>
</table>
== Function ==
[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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
When directed to the nucleus by TGF-beta or BMP signals, Smad proteins undergo cyclin-dependent kinase 8/9 (CDK8/9) and glycogen synthase kinase-3 (GSK3) phosphorylations that mediate the binding of YAP and Pin1 for transcriptional action, and of ubiquitin ligases Smurf1 and Nedd4L for Smad destruction. Here we demonstrate that there is an order of events-Smad activation first and destruction later-and that it is controlled by a switch in the recognition of Smad phosphoserines by WW domains in their binding partners. In the BMP pathway, Smad1 phosphorylation by CDK8/9 creates binding sites for the WW domains of YAP, and subsequent phosphorylation by GSK3 switches off YAP binding and adds binding sites for Smurf1 WW domains. Similarly, in the TGF-beta pathway, Smad3 phosphorylation by CDK8/9 creates binding sites for Pin1 and GSK3, then adds sites to enhance Nedd4L binding. Thus, a Smad phosphoserine code and a set of WW domain code readers provide an efficient solution to the problem of coupling TGF-beta signal delivery to turnover of the Smad signal transducers.

A Smad action turnover switch operated by WW domain readers of a phosphoserine code.,Aragon E, Goerner N, Zaromytidou AI, Xi Q, Escobedo A, Massague J, Macias MJ Genes Dev. 2011 Jun 15;25(12):1275-88. PMID:21685363<ref>PMID:21685363</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2laj" style="background-color:#fffaf0;"></div>

==See Also==
*[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Aragon E]]
[[Category: Escobedo A]]
[[Category: Goerner N]]
[[Category: Macias MJ]]
[[Category: Massague J]]
[[Category: Xi Q]]
[[Category: Zaromytidou A]]