Detail Information for IndEnz0002010486
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;