|
|
| Line 1: |
Line 1: |
| | | | |
| | ==Structure of the second domain of human Nedd4L in complex with a phosphorylated pTPY motif derived from human Smad3== | | ==Structure of the second domain of human Nedd4L in complex with a phosphorylated pTPY motif derived from human Smad3== |
| - | <StructureSection load='2lb2' size='340' side='right'caption='[[2lb2]], [[NMR_Ensembles_of_Models | 25 NMR models]]' scene=''> | + | <StructureSection load='2lb2' size='340' side='right'caption='[[2lb2]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2lb2]] 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=2LB2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2LB2 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2lb2]] 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=2LB2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2LB2 FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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;'>[[2law|2law]], [[2lax|2lax]], [[2lay|2lay]], [[2laz|2laz]], [[2lb0|2lb0]], [[2lb1|2lb1]], [[2lb3|2lb3]]</div></td></tr>
| + | |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NEDD4L, KIAA0439, NEDL3 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=2lb2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2lb2 OCA], [https://pdbe.org/2lb2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2lb2 RCSB], [https://www.ebi.ac.uk/pdbsum/2lb2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2lb2 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=2lb2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2lb2 OCA], [https://pdbe.org/2lb2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2lb2 RCSB], [https://www.ebi.ac.uk/pdbsum/2lb2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2lb2 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[https://www.uniprot.org/uniprot/SMAD3_HUMAN SMAD3_HUMAN]] Defects in SMAD3 may be a cause of colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500]]. Defects in SMAD3 are the cause of Loeys-Dietz syndrome 3 (LDS3) [MIM:[https://omim.org/entry/613795 613795]]. An aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Patients with LDS3 also manifest early-onset osteoarthritis. They lack craniosynostosis and mental retardation. Note=SMAD3 mutations have been reported to be also associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:21778426). This phenotype is distinguised from LDS3 by having aneurysms restricted to thoracic aorta. As individuals carrying these mutations also exhibit aneurysms of other arteries, including abdominal aorta, iliac, and/or intracranial arteries (PubMed:21778426), they have been classified as LDS3 by the OMIM resource.<ref>PMID:21778426</ref> <ref>PMID:21217753</ref> | |
| | == Function == | | == 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> [[https://www.uniprot.org/uniprot/SMAD3_HUMAN SMAD3_HUMAN]] Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF-mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures (By similarity). Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.<ref>PMID:9732876</ref> <ref>PMID:9892009</ref> <ref>PMID:10995748</ref> <ref>PMID:15241418</ref> <ref>PMID:15588252</ref> <ref>PMID:16156666</ref> <ref>PMID:16751101</ref> <ref>PMID:17327236</ref> <ref>PMID:16862174</ref> <ref>PMID:19289081</ref> <ref>PMID:19218245</ref>
| + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 29: |
Line 25: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Aragon, E]] | + | [[Category: Aragon E]] |
| - | [[Category: Escobedo, A]] | + | [[Category: Escobedo A]] |
| - | [[Category: Goerner, N]] | + | [[Category: Goerner N]] |
| - | [[Category: Macias, M J]] | + | [[Category: Macias MJ]] |
| - | [[Category: Massague, J]] | + | [[Category: Massague J]] |
| - | [[Category: Xi, Q]] | + | [[Category: Xi Q]] |
| - | [[Category: Zaromytidou, A]] | + | [[Category: Zaromytidou A]] |
| - | [[Category: Cdk]]
| + | |
| - | [[Category: Nedd4l]]
| + | |
| - | [[Category: Signal transduction]]
| + | |
| - | [[Category: Signaling protein-transcription complex]]
| + | |
| - | [[Category: Smad]]
| + | |
| Structural highlights
Function
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.[1] [2] [3] [4] [5] [6] [7]
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[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Boehmer C, Henke G, Schniepp R, Palmada M, Rothstein JD, Broer S, Lang F. Regulation of the glutamate transporter EAAT1 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid-inducible kinase isoforms SGK1/3 and protein kinase B. J Neurochem. 2003 Sep;86(5):1181-8. PMID:12911626
- ↑ van Bemmelen MX, Rougier JS, Gavillet B, Apotheloz F, Daidie D, Tateyama M, Rivolta I, Thomas MA, Kass RS, Staub O, Abriel H. Cardiac voltage-gated sodium channel Nav1.5 is regulated by Nedd4-2 mediated ubiquitination. Circ Res. 2004 Aug 6;95(3):284-91. Epub 2004 Jun 24. PMID:15217910 doi:10.1161/01.RES.0000136816.05109.89
- ↑ Hryciw DH, Ekberg J, Lee A, Lensink IL, Kumar S, Guggino WB, Cook DI, Pollock CA, Poronnik P. Nedd4-2 functionally interacts with ClC-5: involvement in constitutive albumin endocytosis in proximal tubule cells. J Biol Chem. 2004 Dec 31;279(53):54996-5007. Epub 2004 Oct 15. PMID:15489223 doi:M411491200
- ↑ Henke G, Maier G, Wallisch S, Boehmer C, Lang F. Regulation of the voltage gated K+ channel Kv1.3 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid inducible kinase SGK1. J Cell Physiol. 2004 May;199(2):194-9. PMID:15040001 doi:10.1002/jcp.10430
- ↑ Kuratomi G, Komuro A, Goto K, Shinozaki M, Miyazawa K, Miyazono K, Imamura T. NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-beta (transforming growth factor-beta) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-beta type I receptor. Biochem J. 2005 Mar 15;386(Pt 3):461-70. PMID:15496141 doi:BJ20040738
- ↑ Zhou R, Snyder PM. Nedd4-2 phosphorylation induces serum and glucocorticoid-regulated kinase (SGK) ubiquitination and degradation. J Biol Chem. 2005 Feb 11;280(6):4518-23. Epub 2004 Dec 2. PMID:15576372 doi:10.1074/jbc.M411053200
- ↑ Chan W, Tian R, Lee YF, Sit ST, Lim L, Manser E. Down-regulation of active ACK1 is mediated by association with the E3 ubiquitin ligase Nedd4-2. J Biol Chem. 2009 Mar 20;284(12):8185-94. doi: 10.1074/jbc.M806877200. Epub 2009 , Jan 14. PMID:19144635 doi:10.1074/jbc.M806877200
- ↑ Aragon E, Goerner N, Zaromytidou AI, Xi Q, Escobedo A, Massague J, Macias MJ. A Smad action turnover switch operated by WW domain readers of a phosphoserine code. Genes Dev. 2011 Jun 15;25(12):1275-88. PMID:21685363 doi:10.1101/gad.2060811
|
