IED ID | IndEnz0002010486 |
Enzyme Type ID | protease010486 |
Protein Name |
E3 ubiquitin-protein ligase NEDD4-like EC 2.3.2.26 HECT-type E3 ubiquitin transferase NED4L NEDD4.2 Nedd4-2 |
Gene Name | NEDD4L KIAA0439 NEDL3 |
Organism | Homo sapiens (Human) |
Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
Enzyme Sequence | MATGLGEPVYGLSEDEGESRILRVKVVSGIDLAKKDIFGASDPYVKLSLYVADENRELALVQTKTIKKTLNPKWNEEFYFRVNPSNHRLLFEVFDENRLTRDDFLGQVDVPLSHLPTEDPTMERPYTFKDFLLRPRSHKSRVKGFLRLKMAYMPKNGGQDEENSDQRDDMEHGWEVVDSNDSASQHQEELPPPPLPPGWEEKVDNLGRTYYVNHNNRTTQWHRPSLMDVSSESDNNIRQINQEAAHRRFRSRRHISEDLEPEPSEGGDVPEPWETISEEVNIAGDSLGLALPPPPASPGSRTSPQELSEELSRRLQITPDSNGEQFSSLIQREPSSRLRSCSVTDAVAEQGHLPPPSAPAGRARSSTVTGGEEPTPSVAYVHTTPGLPSGWEERKDAKGRTYYVNHNNRTTTWTRPIMQLAEDGASGSATNSNNHLIEPQIRRPRSLSSPTVTLSAPLEGAKDSPVRRAVKDTLSNPQSPQPSPYNSPKPQHKVTQSFLPPGWEMRIAPNGRPFFIDHNTKTTTWEDPRLKFPVHMRSKTSLNPNDLGPLPPGWEERIHLDGRTFYIDHNSKITQWEDPRLQNPAITGPAVPYSREFKQKYDYFRKKLKKPADIPNRFEMKLHRNNIFEESYRRIMSVKRPDVLKARLWIEFESEKGLDYGGVAREWFFLLSKEMFNPYYGLFEYSATDNYTLQINPNSGLCNEDHLSYFTFIGRVAGLAVFHGKLLDGFFIRPFYKMMLGKQITLNDMESVDSEYYNSLKWILENDPTELDLMFCIDEENFGQTYQVDLKPNGSEIMVTNENKREYIDLVIQWRFVNRVQKQMNAFLEGFTELLPIDLIKIFDENELELLMCGLGDVDVNDWRQHSIYKNGYCPNHPVIQWFWKAVLLMDAEKRIRLLQFVTGTSRVPMNGFAELYGSNGPQLFTIEQWGSPEKLPRAHTCFNRLDLPPYETFEDLREKLLMAVENAQGFEGVD |
Enzyme Length | 975 |
Uniprot Accession Number | Q96PU5 |
Absorption | |
Active Site | ACT_SITE 942; /note=Glycyl thioester intermediate; /evidence=ECO:0000255|PROSITE-ProRule:PRU00104 |
Activity Regulation | ACTIVITY REGULATION: Activated by NDFIP1- and NDFIP2-binding. {ECO:0000269|PubMed:11748237, ECO:0000269|PubMed:26363003}. |
Binding Site | |
Calcium Binding | |
catalytic Activity | CATALYTIC ACTIVITY: Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.; EC=2.3.2.26; Evidence={ECO:0000250|UniProtKB:P46934}; |
DNA Binding | |
EC Number | 2.3.2.26 |
Enzyme Function | 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, SCN2A/Nav1.2, SCN3A/Nav1.3, SCN5A/Nav1.5, SCN9A/Nav1.7, SCN10A/Nav1.8, KCNA3/Kv1.3, KCNH2, EAAT1, KCNQ2/Kv7.2, KCNQ3/Kv7.3 or CLC5 (PubMed:26363003, PubMed:27445338). Promotes ubiquitination and degradation of SGK1 and TNK2. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046). Plays a role in dendrite formation by melanocytes (PubMed:23999003). Involved in the regulation of TOR signaling (PubMed:27694961). Ubiquitinates and regulates protein levels of NTRK1 once this one is activated by NGF (PubMed:27445338). {ECO:0000250|UniProtKB:Q8CFI0, ECO:0000269|PubMed:12911626, ECO:0000269|PubMed:15040001, ECO:0000269|PubMed:15217910, ECO:0000269|PubMed:15489223, ECO:0000269|PubMed:15496141, ECO:0000269|PubMed:15576372, ECO:0000269|PubMed:19144635, ECO:0000269|PubMed:23999003, ECO:0000269|PubMed:25631046, ECO:0000269|PubMed:26363003, ECO:0000269|PubMed:27445338, ECO:0000269|PubMed:27694961}. |
Temperature Dependency | |
PH Dependency | |
Pathway | PATHWAY: Protein modification; protein ubiquitination. |
nucleotide Binding | |
Features | Active site (1); Alternative sequence (5); Beta strand (31); Chain (1); Compositional bias (2); Domain (6); Erroneous initiation (1); Helix (25); Initiator methionine (1); Modified residue (13); Mutagenesis (2); Natural variant (6); Region (5); Sequence caution (1); Sequence conflict (3); Turn (11) |
Keywords | 3D-structure;Acetylation;Alternative splicing;Cytoplasm;Differentiation;Direct protein sequencing;Disease variant;Endosome;Golgi apparatus;Host-virus interaction;Phosphoprotein;Reference proteome;Repeat;Transferase;Ubl conjugation;Ubl conjugation pathway |
Interact With | Q15038; O14669; Q9BZD6; P49281; Q96B67; Q15038; O15105 |
Induction | INDUCTION: By androgens in prostate, and by albumin in kidney. {ECO:0000269|PubMed:14615060, ECO:0000269|PubMed:15489223}. |
Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15496141, ECO:0000269|PubMed:18819914, ECO:0000269|PubMed:27694961}. Golgi apparatus {ECO:0000269|PubMed:26363003}. Endosome, multivesicular body {ECO:0000269|PubMed:26363003}. Note=May be recruited to exosomes by NDFIP1. |
Modified Residue | MOD_RES 2; /note="N-acetylalanine"; /evidence="ECO:0007744|PubMed:22814378"; MOD_RES 312; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:23186163"; MOD_RES 318; /note="Phosphothreonine"; /evidence="ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:23186163"; MOD_RES 342; /note="Phosphoserine; by WNK1 and WNK4"; /evidence="ECO:0000269|PubMed:15328345, ECO:0000269|PubMed:20525693, ECO:0007744|PubMed:18669648"; MOD_RES 367; /note="Phosphothreonine; by SGK1"; /evidence="ECO:0000305|PubMed:15328345"; MOD_RES 446; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:19690332"; MOD_RES 448; /note="Phosphoserine; by PKA and SGK1"; /evidence="ECO:0000269|PubMed:15328345, ECO:0000269|PubMed:15677482, ECO:0007744|PubMed:23186163"; MOD_RES 449; /note="Phosphoserine; by WNK1 and WNK4"; /evidence="ECO:0000269|PubMed:20525693, ECO:0007744|PubMed:18669648"; MOD_RES 464; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:18669648"; MOD_RES 475; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:23186163"; MOD_RES 479; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:17081983, ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"; MOD_RES 483; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"; MOD_RES 487; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:21406692" |
Post Translational Modification | PTM: Phosphorylated by SGK1 or PKA; which impairs interaction with SCNN. Interaction with YWHAH inhibits dephosphorylation. {ECO:0000269|PubMed:11696533, ECO:0000269|PubMed:15328345, ECO:0000269|PubMed:15677482, ECO:0000269|PubMed:20525693, ECO:0000269|PubMed:20730100}.; PTM: Auto-ubiquitinated (PubMed:19343052). Deubiquitinated by USP36, no effect on NEDD4L protein levels. Both proteins interact and regulate each other's ubiquitination levels (PubMed:27445338). {ECO:0000269|PubMed:19343052, ECO:0000269|PubMed:27445338}. |
Signal Peptide | |
Structure 3D | NMR spectroscopy (6); X-ray crystallography (10) |
Cross Reference PDB | 2LAJ; 2LB2; 2LTY; 2MPT; 2NSQ; 2ONI; 3JVZ; 3JW0; 5HPK; 6ZBT; 6ZC9; 7LP1; 7LP3; 7LP4; 7LP5; 7NMZ; |
Mapped Pubmed ID | 10642508; 10720933; 11163210; 11278251; 11742982; 12139396; 12522688; 12646216; 12876068; 15044175; 15231748; 15473846; 16103266; 16169070; 16716084; 16788695; 16954532; 16964398; 17331106; 17487281; 17502380; 17544362; 17652939; 17715136; 18268134; 18293164; 18321968; 18321969; 18498246; 18577513; 18591455; 19028597; 19364400; 19380724; 19381069; 19489725; 19527882; 19615332; 19615732; 19617352; 19635985; 19690890; 19706893; 19874575; 19917253; 19953087; 20003179; 20051513; 20064473; 20090362; 20379614; 20466724; 20504882; 20675381; 20936779; 21052022; 21088674; 21154329; 21176637; 21478478; 21572392; 21685363; 21765395; 21852580; 21900244; 21903422; 21909941; 21988832; 22190034; 22217575; 22361880; 22385262; 22505712; 22762019; 22879586; 22904170; 22921829; 22957059; 23262292; 23305486; 23353631; 23396981; 23549273; 23589291; 23594824; 23792956; 23812770; 24047422; 24284497; 24312311; 24373531; 24446284; 24451387; 24456330; 24657276; 24831004; 25295397; 25416956; 25542253; 25785312; 26130719; 26554540; 26581907; 26608079; 26740304; 26823285; 26949039; 27022162; 27146988; 27339899; 27932573; 28017963; 28608480; 28820317; 29175326; 29505301; 29662198; 30232011; 30287686; 30453017; 30967264; 31320629; 31357244; 31618441; 31673244; 31728037; 31867777; 31900993; 31922594; 31959741; 31993646; 32332792; 32811647; 33045005; 33058421; 33106424; 34284061; 34294877; 34319380; |
Motif | |
Gene Encoded By | |
Mass | 111,932 |
Kinetics | |
Metal Binding | |
Rhea ID | |
Cross Reference Brenda | 2.3.2.26;2.3.2.B8; |