ID:NED4L_HUMAN DESCRIPTION: RecName: Full=E3 ubiquitin-protein ligase NEDD4-like; EC=6.3.2.-; AltName: Full=NEDD4.2; AltName: Full=Nedd4-2; 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 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. ENZYME REGULATION: Activated by NDFIP1- and NDFIP2-binding. PATHWAY: Protein modification; protein ubiquitination. SUBUNIT: Interacts with UBE2E3 (By similarity). Interacts with NDFIP1 and NDFIP2 (By similarity); this interaction activates the E3 ubiquitin-protein ligase. Interacts via its WW domains with SCNN1A, SCNN1B, SCNN1G, SCN1A, SCN2A, SCN3A, SCN5A, SCN8A, SCN9A, SCN10A and CLCN5. Interacts with SMAD2, SMAD3, SMAD6 and SMAD7. The phosphorylated form interacts with 14-3-3 proteins. Interacts with Epstein-Barr virus LMP2A. Interacts with TNK2. Interacts with WNK1. Interacts with SGK1. Interacts (via C2 domain) with NPC2. SUBCELLULAR LOCATION: Cytoplasm. Note=May be recruited to exosomes by NDFIP1. TISSUE SPECIFICITY: Ubiquitously expressed, with highest levels in prostate, pancreas and kidney. INDUCTION: By androgens in prostate, and by albumin in kidney. PTM: Phosphorylated by SGK1 or PKA; which impairs interaction with SCNN. Interaction with YWHAH inhibits dephosphorylation. PTM: Auto-ubiquitinated. SIMILARITY: Contains 1 C2 domain. SIMILARITY: Contains 1 HECT (E6AP-type E3 ubiquitin-protein ligase) domain. SIMILARITY: Contains 4 WW domains. SEQUENCE CAUTION: Sequence=BAA23711.1; Type=Erroneous initiation; Note=Translation N-terminally shortened; Sequence=BAA23711.1; Type=Miscellaneous discrepancy; Note=Probable cloning artifact;
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q96PU5
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0000122 negative regulation of transcription from RNA polymerase II promoter GO:0000209 protein polyubiquitination GO:0003254 regulation of membrane depolarization GO:0006511 ubiquitin-dependent protein catabolic process GO:0006513 protein monoubiquitination GO:0006814 sodium ion transport GO:0006883 cellular sodium ion homeostasis GO:0007588 excretion GO:0010038 response to metal ion GO:0016032 viral process GO:0016567 protein ubiquitination GO:0019058 viral life cycle GO:0030104 water homeostasis GO:0030154 cell differentiation GO:0031647 regulation of protein stability GO:0034220 ion transmembrane transport GO:0034765 regulation of ion transmembrane transport GO:0042176 regulation of protein catabolic process GO:0042391 regulation of membrane potential GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process GO:0045732 positive regulation of protein catabolic process GO:0045807 positive regulation of endocytosis GO:0060306 regulation of membrane repolarization GO:0070936 protein K48-linked ubiquitination GO:0086005 ventricular cardiac muscle cell action potential GO:1901016 regulation of potassium ion transmembrane transporter activity GO:1901017 negative regulation of potassium ion transmembrane transporter activity GO:1901380 negative regulation of potassium ion transmembrane transport GO:1902306 negative regulation of sodium ion transmembrane transport GO:1903861 positive regulation of dendrite extension GO:2000009 negative regulation of protein localization to cell surface GO:2000650 negative regulation of sodium ion transmembrane transporter activity GO:2001288 positive regulation of caveolin-mediated endocytosis
BC032597 - Homo sapiens neural precursor cell expressed, developmentally down-regulated 4-like, mRNA (cDNA clone MGC:44873 IMAGE:5528964), complete cds. AB071179 - Homo sapiens NEDL3 mRNA for NEDD4-like ubiquitin ligase 3, complete cds. DQ890913 - Synthetic construct clone IMAGE:100003543; FLH167042.01X; RZPDo839G0788D neural precursor cell expressed, developmentally down-regulated 4-like (NEDD4L) gene, encodes complete protein. DQ893350 - Synthetic construct clone IMAGE:100005980; FLH196493.01X; RZPDo839E02156D neural precursor cell expressed, developmentally down-regulated 4-like (NEDD4L) gene, encodes complete protein. AY312514 - Homo sapiens NEDD4.2 mRNA, complete cds. AF385931 - Homo sapiens ubiquitin ligase NEDD4Lb (NEDD4L) mRNA, complete cds; alternatively spliced. AY256662 - Homo sapiens NEDD4L variant NEDD4-2C2b (NEDD4-2) mRNA sequence; alternatively spliced. DQ181796 - Homo sapiens NEDD4L variant (NEDD4L) mRNA, complete cds, alternatively spliced. AY112983 - Homo sapiens ubiquitin ligase NEDD4f (NEDD4L) mRNA, complete cds; alternatively spliced. AY112984 - Homo sapiens ubiquitin ligase NEDD4g (NEDD4L) mRNA, complete cds; alternatively spliced. AY112985 - Homo sapiens ubiquitin ligase NEDD4h (NEDD4L) mRNA, complete cds; alternatively spliced. AY243320 - Homo sapiens NEDD4L variant NEDD4-2C1 (NEDD4-2) mRNA sequence; alternatively spliced. AK294963 - Homo sapiens cDNA FLJ61249 complete cds, highly similar to E3 ubiquitin-protein ligase NEDD4-like protein (EC 6.3.2.-). AY243318 - Homo sapiens NEDD4L variant NEDD4-2B (NEDD4-2) mRNA sequence; alternatively spliced. AB007899 - Homo sapiens KIAA0439 mRNA. AY243319 - Homo sapiens NEDD4L variant NEDD4-2A (NEDD4-2) mRNA sequence; alternatively spliced. AK300444 - Homo sapiens cDNA FLJ53199 complete cds, highly similar to E3 ubiquitin-protein ligase NEDD4-like protein (EC 6.3.2.-). AF210730 - Homo sapiens NEDD4La (NEDD4La) mRNA, complete cds. AY243321 - Homo sapiens NEDD4L variant NEDD4-2A2 (NEDD4-2) mRNA sequence; alternatively spliced. AL137469 - Homo sapiens mRNA; cDNA DKFZp434P2422 (from clone DKFZp434P2422); partial cds. LF211076 - JP 2014500723-A/18579: Polycomb-Associated Non-Coding RNAs. JD458374 - Sequence 439398 from Patent EP1572962. JD073824 - Sequence 54848 from Patent EP1572962. JD140017 - Sequence 121041 from Patent EP1572962. JD395157 - Sequence 376181 from Patent EP1572962. AY243322 - Homo sapiens NEDD4L variant NEDD4-2C5 (NEDD4-2) mRNA sequence; alternatively spliced. AY243317 - Homo sapiens NEDD4L variant NEDD4-2C4 (NEDD4-2) mRNA sequence; alternatively spliced. AY243313 - Homo sapiens NEDD4L variant NEDD4-2C2a (NEDD4-2) mRNA, partial cds; alternatively spliced. AY243316 - Homo sapiens NEDD4L variant NEDD4-2C3c (NEDD4-2) mRNA, partial cds; alternatively spliced. AY243314 - Homo sapiens NEDD4L variant NEDD4-2C3a (NEDD4-2) mRNA sequence; alternatively spliced. AY243315 - Homo sapiens NEDD4L variant NEDD4-2C3b (NEDD4-2) mRNA sequence; alternatively spliced. MA446653 - JP 2018138019-A/18579: Polycomb-Associated Non-Coding RNAs. BC000621 - Homo sapiens neural precursor cell expressed, developmentally down-regulated 4-like, mRNA (cDNA clone IMAGE:3346045), partial cds. BC019345 - Homo sapiens, clone IMAGE:3604024, mRNA, partial cds. AB385335 - Synthetic construct DNA, clone: pF1KA0439, Homo sapiens NEDD4L gene for E3 ubiquitin-protein ligase NEDD4-like protein, complete cds, without stop codon, in Flexi system. AY751751 - Homo sapiens NEDD4-2 minus WW2,3 variant (NEDD4L) mRNA, partial cds, alternatively spliced. AK130420 - Homo sapiens cDNA FLJ26910 fis, clone RCT02241, highly similar to Mus musculus neural precursor cell expressed, developmentally down-regulated gene 4-like (Nedd4l). JD021588 - Sequence 2612 from Patent EP1572962. JD029767 - Sequence 10791 from Patent EP1572962. AK091189 - Homo sapiens cDNA FLJ33870 fis, clone CTONG2006691, moderately similar to Ubiquitin--protein ligase (EC 6.3.2.19) NEDD4. JD077677 - Sequence 58701 from Patent EP1572962. JD179911 - Sequence 160935 from Patent EP1572962. JD207203 - Sequence 188227 from Patent EP1572962. JD449469 - Sequence 430493 from Patent EP1572962. JD538197 - Sequence 519221 from Patent EP1572962. JD462827 - Sequence 443851 from Patent EP1572962. JD435072 - Sequence 416096 from Patent EP1572962. JD073035 - Sequence 54059 from Patent EP1572962. AF070601 - Homo sapiens clone 24477 mRNA sequence. JD563137 - Sequence 544161 from Patent EP1572962. JD502665 - Sequence 483689 from Patent EP1572962. JD281298 - Sequence 262322 from Patent EP1572962. JD061197 - Sequence 42221 from Patent EP1572962. JD499063 - Sequence 480087 from Patent EP1572962. JD280472 - Sequence 261496 from Patent EP1572962. JD311447 - Sequence 292471 from Patent EP1572962. JD533584 - Sequence 514608 from Patent EP1572962. JD063509 - Sequence 44533 from Patent EP1572962. JD099704 - Sequence 80728 from Patent EP1572962. JD529824 - Sequence 510848 from Patent EP1572962. JD475370 - Sequence 456394 from Patent EP1572962. JD285868 - Sequence 266892 from Patent EP1572962. JD208368 - Sequence 189392 from Patent EP1572962. JD440512 - Sequence 421536 from Patent EP1572962. JD298153 - Sequence 279177 from Patent EP1572962.
Biochemical and Signaling Pathways
BioCyc Knowledge Library PWY-7511 - protein ubiquitination
Reactome (by CSHL, EBI, and GO)
Protein Q96PU5 (Reactome details) participates in the following event(s):
R-HSA-3159232 Recruitment Of HIV Virion Budding Machinery R-NUL-2176427 NEDD4L ubiquitinates Smad7 and TGFBR1 R-HSA-2176416 NEDD4L ubiquitin ligase binds SMAD7 R-NUL-2176430 NEDD4L binds Smad7 R-HSA-2176491 NEDD4L binds phosphorylated linker region of SMAD2/3 R-HSA-2176502 NEDD4L ubiquitinates SMAD2/3 R-HSA-2176417 SMAD7:NEDD4L complex translocates to the cytosol R-NUL-2176431 Smad7 recruits NEDD4L to activated TGF-beta receptor complex R-NUL-2176428 Translocation of Smad7:NEDD4L complex to the cytosol R-HSA-983157 Interaction of E3 with substrate and E2-Ub complex R-HSA-983147 Release of E3 from polyubiquitinated substrate R-HSA-2169050 SMURFs/NEDD4L ubiquitinate phosphorylated TGFBR1 and SMAD7 R-HSA-983140 Transfer of Ub from E2 to substrate and release of E2 R-HSA-178218 SMAD7:SMURF complex binds to phosphorylated TGFBR1 R-HSA-2682349 RAF1:SGK:TSC22D3:WPP ubiquitinates SCNN channels R-HSA-162588 Budding and maturation of HIV virion R-HSA-2173788 Downregulation of TGF-beta receptor signaling R-HSA-2173795 Downregulation of SMAD2/3:SMAD4 transcriptional activity R-HSA-983168 Antigen processing: Ubiquitination & Proteasome degradation R-HSA-162599 Late Phase of HIV Life Cycle R-HSA-2173789 TGF-beta receptor signaling activates SMADs R-HSA-2173793 Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer R-HSA-983169 Class I MHC mediated antigen processing & presentation R-HSA-162587 HIV Life Cycle R-HSA-170834 Signaling by TGF-beta Receptor Complex R-HSA-212436 Generic Transcription Pathway R-HSA-1280218 Adaptive Immune System R-HSA-2672351 Stimuli-sensing channels R-HSA-162906 HIV Infection R-HSA-9006936 Signaling by TGF-beta family members R-HSA-73857 RNA Polymerase II Transcription R-HSA-168256 Immune System R-HSA-983712 Ion channel transport R-HSA-5663205 Infectious disease R-HSA-162582 Signal Transduction R-HSA-74160 Gene expression (Transcription) R-HSA-382551 Transport of small molecules R-HSA-1643685 Disease
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
