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Identification
HMDB Protein ID HMDBP02282
Secondary Accession Numbers
  • 7767
Name E3 ubiquitin-protein ligase NEDD4-like
Synonyms
  1. NEDD4.2
  2. Nedd4-2
Gene Name NEDD4L
Protein Type Enzyme
Biological Properties
General Function Involved in acid-amino acid ligase activity
Specific Function 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 TGFR1 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 SGK
Pathways Not Available
Reactions Not Available
GO Classification
Component
cell part
intracellular
Function
binding
catalytic activity
ligase activity
protein binding
ligase activity, forming carbon-nitrogen bonds
acid-amino acid ligase activity
Process
metabolic process
macromolecule metabolic process
macromolecule modification
protein modification process
Cellular Location
  1. Cytoplasm
Gene Properties
Chromosome Location Chromosome:1
Locus 18q21
SNPs NEDD4L
Gene Sequence
>2928 bp
ATGGCGACCGGGCTCGGGGAGCCGGTCTATGGACTTTCCGAAGACGAGGGAGAGTCCCGT
ATTCTCAGAGTAAAAGTTGTTTCTGGAATTGATCTCGCCAAAAAGGACATCTTTGGAGCC
AGTGATCCGTATGTGAAACTTTCATTGTACGTAGCGGATGAGAATAGAGAACTTGCTTTG
GTCCAGACAAAAACAATTAAAAAGACACTGAACCCAAAATGGAATGAAGAATTTTATTTC
AGGGTAAACCCATCTAATCACAGACTCCTATTTGAAGTATTTGACGAAAATAGACTGACA
CGAGACGACTTCCTGGGCCAGGTGGACGTGCCCCTTAGTCACCTTCCGACAGAAGATCCA
ACCATGGAGCGACCCTATACATTTAAGGACTTTCTCCTCAGACCAAGAAGTCATAAGTCT
CGAGTTAAGGGATTTTTGCGATTGAAAATGGCCTATATGCCAAAAAATGGAGGTCAAGAT
GAAGAAAACAGTGACCAGAGGGATGACATGGAGCATGGATGGGAAGTTGTTGACTCAAAT
GACTCGGCTTCTCAGCACCAAGAGGAACTTCCTCCTCCTCCTCTGCCTCCCGGGTGGGAA
GAAAAAGTGGACAATTTAGGCCGAACTTACTATGTCAACCACAACAACCGGACCACTCAG
TGGCACAGACCAAGCCTGATGGACGTGTCCTCGGAGTCGGACAATAACATCAGACAGATC
AACCAGGAGGCAGCACACCGGCGCTTCCGCTCCCGCAGGCACATCAGCGAAGACTTGGAG
CCCGAGCCCTCGGAGGGCGGGGATGTCCCCGAGCCTTGGGAGACCATTTCAGAGGAAGTG
AATATCGCTGGAGACTCTCTCGGTCTGGCTCTGCCCCCACCACCGGCCTCCCCAGGATCT
CGGACCAGCCCTCAGGAGCTGTCAGAGGAACTAAGCAGAAGGCTTCAGATCACTCCAGAC
TCCAATGGGGAACAGTTCAGCTCTTTGATTCAAAGAGAACCCTCCTCAAGGTTGAGGTCA
TGCAGTGTCACCGACGCAGTTGCAGAACAGGGCCATCTACCACCGCCCAGTGCCCCAGCT
GGGAGAGCGCGTTCATCAACTGTCACGGGTGGTGAGGAACCAACGCCATCAGTGGCCTAT
GTACATACCACGCCGGGTCTGCCTTCAGGCTGGGAAGAAAGAAAAGATGCTAAGGGGCGC
ACATACTATGTCAATCATAACAATCGAACCACAACTTGGACTCGACCTATCATGCAGCTT
GCAGAAGATGGTGCGTCCGGATCAGCCACAAACAGTAACAACCATCTAATCGAGCCTCAG
ATCCGCCGGCCTCGTAGCCTCAGCTCGCCAACAGTAACTTTATCTGCCCCGCTGGAGGGT
GCCAAGGACTCACCCGTACGTCGGGCTGTGAAAGACACCCTTTCCAACCCACAGTCCCCA
CAGCCATCACCTTACAACTCCCCCAAACCACAACACAAAGTCACACAGAGCTTCTTGCCA
CCCGGCTGGGAAATGAGGATAGCGCCAAACGGCCGGCCCTTCTTCATTGATCATAACACA
AAGACTACAACCTGGGAAGATCCACGTTTGAAATTTCCAGTACATATGCGGTCAAAGACA
TCTTTAAACCCCAATGACCTTGGCCCCCTTCCTCCTGGCTGGGAAGAAAGAATTCACTTG
GATGGCCGAACGTTTTATATTGATCATAATAGCAAAATTACTCAGTGGGAAGACCCAAGA
CTGCAGAACCCAGCTATTACTGGTCCGGCTGTCCCTTACTCCAGAGAATTTAAGCAGAAA
TATGACTACTTCAGGAAGAAATTAAAGAAACCTGCTGATATCCCCAATAGGTTTGAAATG
AAACTTCACAGAAATAACATATTTGAAGAGTCCTATCGGAGAATTATGTCCGTGAAAAGA
CCAGATGTCCTAAAAGCTAGACTGTGGATTGAGTTTGAATCAGAGAAAGGTCTTGACTAT
GGGGGTGTGGCCAGAGAATGGTTCTTCTTACTGTCCAAAGAGATGTTCAACCCCTACTAC
GGCCTCTTTGAGTACTCTGCCACGGACAACTACACCCTTCAGATCAACCCTAATTCAGGC
CTCTGTAATGAGGATCATTTGTCCTACTTCACTTTTATTGGAAGAGTTGCTGGTCTGGCC
GTATTTCATGGGAAGCTCTTAGATGGTTTCTTCATTAGACCATTTTACAAGATGATGTTG
GGAAAGCAGATAACCCTGAATGACATGGAATCTGTGGATAGTGAATATTACAACTCTTTG
AAATGGATCCTGGAGAATGACCCTACTGAGCTGGACCTCATGTTCTGCATAGACGAAGAA
AACTTTGGACAGACATATCAAGTGGATTTGAAGCCCAATGGGTCAGAAATAATGGTCACA
AATGAAAACAAAAGGGAATATATCGACTTAGTCATCCAGTGGAGATTTGTGAACAGGGTC
CAGAAGCAGATGAACGCCTTCTTGGAGGGATTCACAGAACTACTTCCTATTGATTTGATT
AAAATTTTTGATGAAAATGAGCTGGAGTTGCTCATGTGCGGCCTCGGTGATGTGGATGTG
AATGACTGGAGACAGCATTCTATTTACAAGAACGGCTACTGCCCAAACCACCCCGTCATT
CAGTGGTTCTGGAAGGCTGTGCTACTCATGGACGCCGAAAAGCGTATCCGGTTACTGCAG
TTTGTCACAGGGACATCGCGAGTACCTATGAATGGATTTGCCGAACTTTATGGTTCCAAT
GGTCCTCAGCTGTTTACAATAGAGCAATGGGGCAGTCCTGAGAAACTGCCCAGAGCTCAC
ACATGCTTTAATCGCCTTGACTTACCTCCATATGAAACCTTTGAAGATTTACGAGAGAAA
CTTCTCATGGCCGTGGAAAATGCTCAAGGATTTGAAGGGGTGGATTAA
Protein Properties
Number of Residues 975
Molecular Weight 111930.9
Theoretical pI 5.6
Pfam Domain Function
Signals
  • None
Transmembrane Regions
  • None
Protein Sequence
>E3 ubiquitin-protein ligase NEDD4-like
MATGLGEPVYGLSEDEGESRILRVKVVSGIDLAKKDIFGASDPYVKLSLYVADENRELAL
VQTKTIKKTLNPKWNEEFYFRVNPSNHRLLFEVFDENRLTRDDFLGQVDVPLSHLPTEDP
TMERPYTFKDFLLRPRSHKSRVKGFLRLKMAYMPKNGGQDEENSDQRDDMEHGWEVVDSN
DSASQHQEELPPPPLPPGWEEKVDNLGRTYYVNHNNRTTQWHRPSLMDVSSESDNNIRQI
NQEAAHRRFRSRRHISEDLEPEPSEGGDVPEPWETISEEVNIAGDSLGLALPPPPASPGS
RTSPQELSEELSRRLQITPDSNGEQFSSLIQREPSSRLRSCSVTDAVAEQGHLPPPSAPA
GRARSSTVTGGEEPTPSVAYVHTTPGLPSGWEERKDAKGRTYYVNHNNRTTTWTRPIMQL
AEDGASGSATNSNNHLIEPQIRRPRSLSSPTVTLSAPLEGAKDSPVRRAVKDTLSNPQSP
QPSPYNSPKPQHKVTQSFLPPGWEMRIAPNGRPFFIDHNTKTTTWEDPRLKFPVHMRSKT
SLNPNDLGPLPPGWEERIHLDGRTFYIDHNSKITQWEDPRLQNPAITGPAVPYSREFKQK
YDYFRKKLKKPADIPNRFEMKLHRNNIFEESYRRIMSVKRPDVLKARLWIEFESEKGLDY
GGVAREWFFLLSKEMFNPYYGLFEYSATDNYTLQINPNSGLCNEDHLSYFTFIGRVAGLA
VFHGKLLDGFFIRPFYKMMLGKQITLNDMESVDSEYYNSLKWILENDPTELDLMFCIDEE
NFGQTYQVDLKPNGSEIMVTNENKREYIDLVIQWRFVNRVQKQMNAFLEGFTELLPIDLI
KIFDENELELLMCGLGDVDVNDWRQHSIYKNGYCPNHPVIQWFWKAVLLMDAEKRIRLLQ
FVTGTSRVPMNGFAELYGSNGPQLFTIEQWGSPEKLPRAHTCFNRLDLPPYETFEDLREK
LLMAVENAQGFEGVD
GenBank ID Protein 222352086
UniProtKB/Swiss-Prot ID Q96PU5
UniProtKB/Swiss-Prot Entry Name NED4L_HUMAN
PDB IDs Not Available
GenBank Gene ID NM_001144967.1
GeneCard ID NEDD4L
GenAtlas ID NEDD4L
HGNC ID HGNC:7728
References
General References
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  2. Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP: A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10762-7. doi: 10.1073/pnas.0805139105. Epub 2008 Jul 31. [PubMed:18669648 ]
  3. Mayya V, Lundgren DH, Hwang SI, Rezaul K, Wu L, Eng JK, Rodionov V, Han DK: Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions. Sci Signal. 2009 Aug 18;2(84):ra46. doi: 10.1126/scisignal.2000007. [PubMed:19690332 ]
  4. Daub H, Olsen JV, Bairlein M, Gnad F, Oppermann FS, Korner R, Greff Z, Keri G, Stemmann O, Mann M: Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol Cell. 2008 Aug 8;31(3):438-48. doi: 10.1016/j.molcel.2008.07.007. [PubMed:18691976 ]
  5. Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M: Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell. 2006 Nov 3;127(3):635-48. [PubMed:17081983 ]
  6. Gauci S, Helbig AO, Slijper M, Krijgsveld J, Heck AJ, Mohammed S: Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach. Anal Chem. 2009 Jun 1;81(11):4493-501. doi: 10.1021/ac9004309. [PubMed:19413330 ]
  7. Bechtel S, Rosenfelder H, Duda A, Schmidt CP, Ernst U, Wellenreuther R, Mehrle A, Schuster C, Bahr A, Blocker H, Heubner D, Hoerlein A, Michel G, Wedler H, Kohrer K, Ottenwalder B, Poustka A, Wiemann S, Schupp I: The full-ORF clone resource of the German cDNA Consortium. BMC Genomics. 2007 Oct 31;8:399. [PubMed:17974005 ]
  8. Ishikawa K, Nagase T, Nakajima D, Seki N, Ohira M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O: Prediction of the coding sequences of unidentified human genes. VIII. 78 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 1997 Oct 31;4(5):307-13. [PubMed:9455477 ]
  9. Snyder PM, Olson DR, Thomas BC: Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ channel. J Biol Chem. 2002 Jan 4;277(1):5-8. Epub 2001 Nov 5. [PubMed:11696533 ]
  10. 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. [PubMed:12911626 ]
  11. 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. [PubMed:15040001 ]
  12. 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. [PubMed:15576372 ]
  13. Chen H, Ross CA, Wang N, Huo Y, MacKinnon DF, Potash JB, Simpson SG, McMahon FJ, DePaulo Jr JR, McInnis MG: NEDD4L on human chromosome 18q21 has multiple forms of transcripts and is a homologue of the mouse Nedd4-2 gene. Eur J Hum Genet. 2001 Dec;9(12):922-30. [PubMed:11840194 ]
  14. Malbert-Colas L, Nicolas G, Galand C, Lecomte MC, Dhermy D: Identification of new partners of the epithelial sodium channel alpha subunit. C R Biol. 2003 Jul;326(7):615-24. [PubMed:14556380 ]
  15. Qi H, Grenier J, Fournier A, Labrie C: Androgens differentially regulate the expression of NEDD4L transcripts in LNCaP human prostate cancer cells. Mol Cell Endocrinol. 2003 Nov 28;210(1-2):51-62. [PubMed:14615060 ]
  16. Ichimura T, Yamamura H, Sasamoto K, Tominaga Y, Taoka M, Kakiuchi K, Shinkawa T, Takahashi N, Shimada S, Isobe T: 14-3-3 proteins modulate the expression of epithelial Na+ channels by phosphorylation-dependent interaction with Nedd4-2 ubiquitin ligase. J Biol Chem. 2005 Apr 1;280(13):13187-94. Epub 2005 Jan 26. [PubMed:15677482 ]
  17. Winberg G, Matskova L, Chen F, Plant P, Rotin D, Gish G, Ingham R, Ernberg I, Pawson T: Latent membrane protein 2A of Epstein-Barr virus binds WW domain E3 protein-ubiquitin ligases that ubiquitinate B-cell tyrosine kinases. Mol Cell Biol. 2000 Nov;20(22):8526-35. [PubMed:11046148 ]
  18. Harvey KF, Shearwin-Whyatt LM, Fotia A, Parton RG, Kumar S: N4WBP5, a potential target for ubiquitination by the Nedd4 family of proteins, is a novel Golgi-associated protein. J Biol Chem. 2002 Mar 15;277(11):9307-17. Epub 2001 Dec 17. [PubMed:11748237 ]
  19. 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. [PubMed:15217910 ]
  20. 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. [PubMed:15489223 ]
  21. Snyder PM, Olson DR, Kabra R, Zhou R, Steines JC: cAMP and serum and glucocorticoid-inducible kinase (SGK) regulate the epithelial Na(+) channel through convergent phosphorylation of Nedd4-2. J Biol Chem. 2004 Oct 29;279(44):45753-8. Epub 2004 Aug 24. [PubMed:15328345 ]
  22. Rougier JS, van Bemmelen MX, Bruce MC, Jespersen T, Gavillet B, Apotheloz F, Cordonier S, Staub O, Rotin D, Abriel H: Molecular determinants of voltage-gated sodium channel regulation by the Nedd4/Nedd4-like proteins. Am J Physiol Cell Physiol. 2005 Mar;288(3):C692-701. Epub 2004 Nov 17. [PubMed:15548568 ]
  23. 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. [PubMed:15496141 ]
  24. Putz U, Howitt J, Lackovic J, Foot N, Kumar S, Silke J, Tan SS: Nedd4 family-interacting protein 1 (Ndfip1) is required for the exosomal secretion of Nedd4 family proteins. J Biol Chem. 2008 Nov 21;283(47):32621-7. doi: 10.1074/jbc.M804120200. Epub 2008 Sep 25. [PubMed:18819914 ]
  25. Mund T, Pelham HR: Control of the activity of WW-HECT domain E3 ubiquitin ligases by NDFIP proteins. EMBO Rep. 2009 May;10(5):501-7. doi: 10.1038/embor.2009.30. Epub 2009 Apr 3. [PubMed:19343052 ]
  26. Fouladkou F, Alikhani-Koopaei R, Vogt B, Flores SY, Malbert-Colas L, Lecomte MC, Loffing J, Frey FJ, Frey BM, Staub O: A naturally occurring human Nedd4-2 variant displays impaired ENaC regulation in Xenopus laevis oocytes. Am J Physiol Renal Physiol. 2004 Sep;287(3):F550-61. Epub 2004 May 12. [PubMed:15140763 ]