2m3o

From Proteopedia

(Difference between revisions)

Revision as of 13:27, 22 February 2023

Structure and dynamics of a human Nedd4 WW domain-ENaC complex

Structural highlights

2m3o is a 2 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NEDD4_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. Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity. Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes. Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes. According to PubMed:18562292 the direct link between NEDD4 and PTEN regulation through polyubiquitination described in PubMed:17218260 is questionable. Involved in ubiquitination of ERBB4 intracellular domain E4ICD. Involved in the budding of many viruses. 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.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

Nedd4-1 (neuronal precursor cell expressed developmentally downregulated gene 4-1) is an E3 ubiquitin ligase that interacts with and negatively regulates the epithelial Na(+) channel (ENaC). The WW domains of Nedd4-1 bind to the ENaC subunits via recognition of PY motifs. Human Nedd4-1 (hNedd4-1) contains four WW domains with the third domain (WW3*) showing the strongest affinity to the PY motif. To understand the mechanism underlying this binding affinity, we have carried out NMR structural and dynamics analyses of the hNedd4-1 WW3* domain in complex with a peptide comprising the C-terminal tail of the human ENaC alpha-subunit. The structure reveals that the peptide interacts in a similar manner to other WW domain-ENaC peptide structures. Crucial interactions that likely provide binding affinity are the broad XP groove facilitating additional contacts between the WW3* domain and the peptide, compared to similar complexes, and the large surface area buried (83A(2)) between R430 (WW3*) and L647' (alphaENaC). This corroborates the model-free analysis of the (15)N backbone relaxation data, which showed that R430 is the most rigid residue in the domain (S(2)=0.90+/-0.01). Carr-Purcell-Meiboom-Gill relaxation dispersion analysis identified two different conformational exchange processes on the mus-ms time-scale. One of these processes involves residues located at the peptide binding interface, suggesting conformational exchange may play a role in peptide recognition. Thus, both structural and dynamic features of the complex appear to define the high binding affinity. The results should aid interpretation of biochemical data and modeling interfaces between Nedd4-1 and other interacting proteins.

Structure and dynamics of human Nedd4-1 WW3 in complex with the alphaENaC PY motif.,Bobby R, Medini K, Neudecker P, Lee TV, Brimble MA, McDonald FJ, Lott JS, Dingley AJ Biochim Biophys Acta. 2013 Aug;1834(8):1632-41. doi:, 10.1016/j.bbapap.2013.04.031. Epub 2013 May 8. PMID:23665454^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Wang X, Trotman LC, Koppie T, Alimonti A, Chen Z, Gao Z, Wang J, Erdjument-Bromage H, Tempst P, Cordon-Cardo C, Pandolfi PP, Jiang X. NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell. 2007 Jan 12;128(1):129-39. PMID:17218260 doi:10.1016/j.cell.2006.11.039
↑ Fouladkou F, Landry T, Kawabe H, Neeb A, Lu C, Brose N, Stambolic V, Rotin D. The ubiquitin ligase Nedd4-1 is dispensable for the regulation of PTEN stability and localization. Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8585-90. doi:, 10.1073/pnas.0803233105. Epub 2008 Jun 18. PMID:18562292 doi:10.1073/pnas.0803233105
↑ Lin Q, Wang J, Childress C, Sudol M, Carey DJ, Yang W. HECT E3 ubiquitin ligase Nedd4-1 ubiquitinates ACK and regulates epidermal growth factor (EGF)-induced degradation of EGF receptor and ACK. Mol Cell Biol. 2010 Mar;30(6):1541-54. doi: 10.1128/MCB.00013-10. Epub 2010 Jan, 19. PMID:20086093 doi:10.1128/MCB.00013-10
↑ Persaud A, Alberts P, Hayes M, Guettler S, Clarke I, Sicheri F, Dirks P, Ciruna B, Rotin D. Nedd4-1 binds and ubiquitylates activated FGFR1 to control its endocytosis and function. EMBO J. 2011 Jul 15;30(16):3259-73. doi: 10.1038/emboj.2011.234. PMID:21765395 doi:10.1038/emboj.2011.234
↑ Maspero E, Mari S, Valentini E, Musacchio A, Fish A, Pasqualato S, Polo S. Structure of the HECT:ubiquitin complex and its role in ubiquitin chain elongation. EMBO Rep. 2011 Mar 11. PMID:21399620 doi:10.1038/embor.2011.21
↑ Bobby R, Medini K, Neudecker P, Lee TV, Brimble MA, McDonald FJ, Lott JS, Dingley AJ. Structure and dynamics of human Nedd4-1 WW3 in complex with the alphaENaC PY motif. Biochim Biophys Acta. 2013 Aug;1834(8):1632-41. doi:, 10.1016/j.bbapap.2013.04.031. Epub 2013 May 8. PMID:23665454 doi:10.1016/j.bbapap.2013.04.031

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2m3o"

@@ Line 1: / Line 1: @@
 ==Structure and dynamics of a human Nedd4 WW domain-ENaC complex==
-<StructureSection load='2m3o' size='340' side='right'caption='[[2m3o]], [[NMR_Ensembles_of_Models | 15 NMR models]]' scene=''>
+<StructureSection load='2m3o' size='340' side='right'caption='[[2m3o]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2m3o]] 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=2M3O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2M3O FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2m3o]] 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=2M3O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2M3O FirstGlance]. <br>
-</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1i5h|1i5h]], [[2ez5|2ez5]]</div></td></tr>
+</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=2m3o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2m3o OCA], [https://pdbe.org/2m3o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2m3o RCSB], [https://www.ebi.ac.uk/pdbsum/2m3o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2m3o ProSAT]</span></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NEDD4, KIAA0093, NEDD4-1, PIG53 ([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=2m3o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2m3o OCA], [https://pdbe.org/2m3o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2m3o RCSB], [https://www.ebi.ac.uk/pdbsum/2m3o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2m3o ProSAT]</span></td></tr>
 </table>
-== Disease ==
-[[https://www.uniprot.org/uniprot/SCNNA_HUMAN SCNNA_HUMAN]] Idiopathic bronchiectasis;Generalized pseudohypoaldosteronism type 1. The disease is caused by mutations affecting the gene represented in this entry. The degree of channel function impairment differentially affects the renin-aldosterone system and urinary Na/K ratios, resulting in distinct genotype-phenotype relationships in PHA1 patients. Loss-of-function mutations are associated with a severe clinical course and age-dependent hyperactivation of the renin-aldosterone system. This feature is not observed in patients with missense mutations that reduce but do not eliminate channel function. Markedly reduced channel activity results in impaired linear growth and delayed puberty (PubMed:18634878).  The disease is caused by mutations affecting the gene represented in this entry.
 == Function ==
-[[https://www.uniprot.org/uniprot/NEDD4_HUMAN NEDD4_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. Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity. Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes. Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes. According to PubMed:18562292 the direct link between NEDD4 and PTEN regulation through polyubiquitination described in PubMed:17218260 is questionable. Involved in ubiquitination of ERBB4 intracellular domain E4ICD. Involved in the budding of many viruses. 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.<ref>PMID:17218260</ref> <ref>PMID:18562292</ref> <ref>PMID:20086093</ref> <ref>PMID:21765395</ref> <ref>PMID:21399620</ref>  [[https://www.uniprot.org/uniprot/SCNNA_HUMAN SCNNA_HUMAN]] Sodium permeable non-voltage-sensitive ion channel inhibited by the diuretic amiloride. Mediates the electrodiffusion of the luminal sodium (and water, which follows osmotically) through the apical membrane of epithelial cells. Controls the reabsorption of sodium in kidney, colon, lung and sweat glands. Also plays a role in taste perception.
+[https://www.uniprot.org/uniprot/NEDD4_HUMAN NEDD4_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. Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity. Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes. Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes. According to PubMed:18562292 the direct link between NEDD4 and PTEN regulation through polyubiquitination described in PubMed:17218260 is questionable. Involved in ubiquitination of ERBB4 intracellular domain E4ICD. Involved in the budding of many viruses. 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.<ref>PMID:17218260</ref> <ref>PMID:18562292</ref> <ref>PMID:20086093</ref> <ref>PMID:21765395</ref> <ref>PMID:21399620</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 28: / Line 24: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Bobby, R]]
+[[Category: Bobby R]]
-[[Category: Brimble, M A]]
+[[Category: Brimble MA]]
-[[Category: Dingley, A J]]
+[[Category: Dingley AJ]]
-[[Category: Lee, V]]
+[[Category: Lee V]]
-[[Category: Lott, J]]
+[[Category: Lott J]]
-[[Category: MacDonald, F J]]
+[[Category: MacDonald FJ]]
-[[Category: Medini, K]]
+[[Category: Medini K]]
-[[Category: Neudecker, P]]
+[[Category: Neudecker P]]
-[[Category: Enac]]
-[[Category: Peptide binding protein-protein binding complex]]
-[[Category: Ubiquitin e3 ligase]]
-[[Category: Ww domain]]

2m3o

From Proteopedia

Revision as of 13:27, 22 February 2023

Structure and dynamics of a human Nedd4 WW domain-ENaC complex

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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