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| | ==Solution Structure of the rNedd4 WW2 Domain-Cx43CT Peptide Complex by NMR== | | ==Solution Structure of the rNedd4 WW2 Domain-Cx43CT Peptide Complex by NMR== |
| - | <StructureSection load='2n8t' size='340' side='right' caption='[[2n8t]], [[NMR_Ensembles_of_Models | 10 NMR models]]' scene=''> | + | <StructureSection load='2n8t' size='340' side='right'caption='[[2n8t]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2n8t]] is a 2 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N8T OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2N8T FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2n8t]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N8T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2N8T FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 10 models</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2n8s|2n8s]], [[2n8u|2n8u]]</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2n8t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n8t OCA], [http://pdbe.org/2n8t PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2n8t RCSB], [http://www.ebi.ac.uk/pdbsum/2n8t PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2n8t 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=2n8t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n8t OCA], [https://pdbe.org/2n8t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2n8t RCSB], [https://www.ebi.ac.uk/pdbsum/2n8t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2n8t ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/NEDD4_RAT NEDD4_RAT]] 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. Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes. Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes. Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity. Is involved in ubiquitination of ERBB4 intracellular domain E4ICD. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. Ubiquitinates TNK2 and regulates EGF-induced degradation of EGFR and TNF2 (By similarity).<ref>PMID:20159449</ref> [[http://www.uniprot.org/uniprot/CXA1_RAT CXA1_RAT]] Gap junction protein that acts as a regulator of bladder capacity. A gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell. Negative regulator of bladder functional capacity: acts by enhancing intercellular electrical and chemical transmission, thus sensitizing bladder muscles to cholinergic neural stimuli and causing them to contract (By similarity). | + | [https://www.uniprot.org/uniprot/NEDD4_RAT NEDD4_RAT] 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. Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes. Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes. Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity. Is involved in ubiquitination of ERBB4 intracellular domain E4ICD. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. Ubiquitinates TNK2 and regulates EGF-induced degradation of EGFR and TNF2 (By similarity).<ref>PMID:20159449</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Ubiquitin protein ligase|Ubiquitin protein ligase]] | + | *[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Kieken, F]] | + | [[Category: Large Structures]] |
| - | [[Category: Sorgen, P L]] | + | [[Category: Rattus norvegicus]] |
| - | [[Category: Spagnol, G]] | + | [[Category: Kieken F]] |
| - | [[Category: Cx43ct]] | + | [[Category: Sorgen PL]] |
| - | [[Category: Ligase]] | + | [[Category: Spagnol G]] |
| - | [[Category: Ligase-peptide complex]]
| + | |
| - | [[Category: Phosphorylation]]
| + | |
| - | [[Category: Rnedd4 ww2]]
| + | |
| Structural highlights
Function
NEDD4_RAT 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. Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes. Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes. Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity. Is involved in ubiquitination of ERBB4 intracellular domain E4ICD. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. Ubiquitinates TNK2 and regulates EGF-induced degradation of EGFR and TNF2 (By similarity).[1]
Publication Abstract from PubMed
Nedd4 was the first ubiquitin protein ligase identified to interact with Cx43 and its suppressed expression results in accumulation of gap junction plaques at the plasma membrane. Nedd4-mediated ubiquitination of Cx43 is required to recruit Eps15 and target Cx43 to the endocytic pathway. While the Cx43 residues that undergo ubiquitination are still unknown, in this study we address other unresolved questions pertaining to the molecular mechanisms mediating the direct interaction between Nedd4 (WW1-3 domains) and Cx43 (carboxyl terminus, CT). All three WW domains display a similar three antiparallel beta-strand structure and interact with the same Cx43CT 283PPxY286 sequence. While Y286 is essential for the interaction, MAPK phosphorylation of the preceding serine residues (pS282 and pS279) increases the binding affinity by two-fold for the WW domains (WW2>WW3>>WW1). The structure of the WW2/Cx43CTpS282,pS279 complex reveals that coordination of pS282 with the end of beta strand 3 enables pS279 to interact with the back face of beta strand 3 (Y286 is on the front face) and loop 2, forming a horseshoe-shaped structure. The close sequence identity of WW2 with WW1 and WW3 residues that interact with the Cx43CT PPxY motif and pS282/pS279 strongly suggest that the significantly lower binding affinity of WW1 is the result of a more rigid structure. This study presents the first structure illustrating how phosphorylation of the Cx43CT domain helps mediate the interaction with a molecular partner involved in gap junction regulation.
Structural Studies of the Nedd4 WW Domains and their Selectivity for the Cx43 Carboxyl-terminus.,Spagnol G, Kieken F, Kopanic JL, Li H, Zach S, Stauch KL, Grosely R, Sorgen PL J Biol Chem. 2016 Feb 3. pii: jbc.M115.701417. PMID:26841867[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kawabe H, Neeb A, Dimova K, Young SM Jr, Takeda M, Katsurabayashi S, Mitkovski M, Malakhova OA, Zhang DE, Umikawa M, Kariya K, Goebbels S, Nave KA, Rosenmund C, Jahn O, Rhee J, Brose N. Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls neurite development. Neuron. 2010 Feb 11;65(3):358-72. doi: 10.1016/j.neuron.2010.01.007. PMID:20159449 doi:10.1016/j.neuron.2010.01.007
- ↑ Spagnol G, Kieken F, Kopanic JL, Li H, Zach S, Stauch KL, Grosely R, Sorgen PL. Structural Studies of the Nedd4 WW Domains and their Selectivity for the Cx43 Carboxyl-terminus. J Biol Chem. 2016 Feb 3. pii: jbc.M115.701417. PMID:26841867 doi:http://dx.doi.org/10.1074/jbc.M115.701417
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