UniProt functional annotation for Q96PU5



	UniProt functional annotation for Q96PU5

UniProt code: Q96PU5.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

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}.

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;

Activity regulation: Activated by NDFIP1- and NDFIP2-binding.

Pathway: Protein modification; protein ubiquitination.

Subunit: Interacts with UBE2E3 (By similarity). Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase (PubMed:26363003, PubMed:11748237). Interacts via its WW domains with SCNN1A, SCNN1B, SCNN1G, SCN1A, SCN2A, SCN3A, SCN5A, SCN8A, SCN9A, SCN10A and CLCN5 (PubMed:11696533, PubMed:14556380, PubMed:15217910, PubMed:15489223, PubMed:15548568). Interacts with SMAD2, SMAD3, SMAD6 and SMAD7 (PubMed:15496141). The phosphorylated form interacts with 14- 3-3 proteins (PubMed:15677482). Interacts with TNK2 (PubMed:19144635, PubMed:20086093). Interacts with WNK1 (PubMed:20525693). Interacts with SGK1 (PubMed:11696533, PubMed:20730100). Interacts (via C2 domain) with NPC2 (PubMed:19664597). Interacts with ARRDC4 (PubMed:23236378). Interacts with KCNQ1; promotes internalization of KCNQ1 (PubMed:22024150). Interacts (via domains WW1, 3 and 4) with USP36; the interaction inhibits ubiquitination of, at least, NTRK1, KCNQ2 and KCNQ3 by NEDD4L (PubMed:27445338). Interacts with PRRG4 (via cytoplasmic domain) (PubMed:23873930). {ECO:0000250|UniProtKB:Q8CFI0, ECO:0000269|PubMed:11696533, ECO:0000269|PubMed:11748237, ECO:0000269|PubMed:14556380, ECO:0000269|PubMed:15217910, ECO:0000269|PubMed:15489223, ECO:0000269|PubMed:15496141, ECO:0000269|PubMed:15548568, ECO:0000269|PubMed:15677482, ECO:0000269|PubMed:19144635, ECO:0000269|PubMed:19664597, ECO:0000269|PubMed:20086093, ECO:0000269|PubMed:20525693, ECO:0000269|PubMed:20730100, ECO:0000269|PubMed:22024150, ECO:0000269|PubMed:23236378, ECO:0000269|PubMed:23873930, ECO:0000269|PubMed:26363003, ECO:0000269|PubMed:27445338}.

Subunit: (Microbial infection) Interacts with Epstein-Barr virus LMP2A. {ECO:0000269|PubMed:11046148}.

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.

Tissue specificity: Ubiquitously expressed, with highest levels in prostate, pancreas and kidney (PubMed:14615060, PubMed:15496141, PubMed:19664597). Expressed in melanocytes (PubMed:23999003). {ECO:0000269|PubMed:14615060, ECO:0000269|PubMed:15496141, ECO:0000269|PubMed:19664597, ECO:0000269|PubMed:23999003}.

Induction: By androgens in prostate, and by albumin in kidney. {ECO:0000269|PubMed:14615060, ECO:0000269|PubMed:15489223}.

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}.

Disease: Periventricular nodular heterotopia 7 (PVNH7) [MIM:617201]: A form of periventricular nodular heterotopia, a disorder resulting from a defect in the pattern of neuronal migration in which ectopic collections of neurons lie along the lateral ventricles of the brain or just beneath, contiguously or in isolated patches. PVNH7 is an autosomal dominant disease characterized by delayed psychomotor development, intellectual disability, and seizures in some patients. Additional features include cleft palate and toe syndactyly. {ECO:0000269|PubMed:27694961}. Note=The disease is caused by variants affecting the gene represented in this entry.

Sequence caution: Sequence=BAA23711.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; Sequence=BAA23711.1; Type=Miscellaneous discrepancy; Note=Probable cloning artifact.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



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}.


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;
Activity regulation:		Activated by NDFIP1- and NDFIP2-binding.
Pathway:		Protein modification; protein ubiquitination.
Subunit:		Interacts with UBE2E3 (By similarity). Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase (PubMed:26363003, PubMed:11748237). Interacts via its WW domains with SCNN1A, SCNN1B, SCNN1G, SCN1A, SCN2A, SCN3A, SCN5A, SCN8A, SCN9A, SCN10A and CLCN5 (PubMed:11696533, PubMed:14556380, PubMed:15217910, PubMed:15489223, PubMed:15548568). Interacts with SMAD2, SMAD3, SMAD6 and SMAD7 (PubMed:15496141). The phosphorylated form interacts with 14- 3-3 proteins (PubMed:15677482). Interacts with TNK2 (PubMed:19144635, PubMed:20086093). Interacts with WNK1 (PubMed:20525693). Interacts with SGK1 (PubMed:11696533, PubMed:20730100). Interacts (via C2 domain) with NPC2 (PubMed:19664597). Interacts with ARRDC4 (PubMed:23236378). Interacts with KCNQ1; promotes internalization of KCNQ1 (PubMed:22024150). Interacts (via domains WW1, 3 and 4) with USP36; the interaction inhibits ubiquitination of, at least, NTRK1, KCNQ2 and KCNQ3 by NEDD4L (PubMed:27445338). Interacts with PRRG4 (via cytoplasmic domain) (PubMed:23873930). {ECO:0000250\|UniProtKB:Q8CFI0, ECO:0000269\|PubMed:11696533, ECO:0000269\|PubMed:11748237, ECO:0000269\|PubMed:14556380, ECO:0000269\|PubMed:15217910, ECO:0000269\|PubMed:15489223, ECO:0000269\|PubMed:15496141, ECO:0000269\|PubMed:15548568, ECO:0000269\|PubMed:15677482, ECO:0000269\|PubMed:19144635, ECO:0000269\|PubMed:19664597, ECO:0000269\|PubMed:20086093, ECO:0000269\|PubMed:20525693, ECO:0000269\|PubMed:20730100, ECO:0000269\|PubMed:22024150, ECO:0000269\|PubMed:23236378, ECO:0000269\|PubMed:23873930, ECO:0000269\|PubMed:26363003, ECO:0000269\|PubMed:27445338}.
Subunit:		(Microbial infection) Interacts with Epstein-Barr virus LMP2A. {ECO:0000269\|PubMed:11046148}.
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.
Tissue specificity:		Ubiquitously expressed, with highest levels in prostate, pancreas and kidney (PubMed:14615060, PubMed:15496141, PubMed:19664597). Expressed in melanocytes (PubMed:23999003). {ECO:0000269\|PubMed:14615060, ECO:0000269\|PubMed:15496141, ECO:0000269\|PubMed:19664597, ECO:0000269\|PubMed:23999003}.
Induction:		By androgens in prostate, and by albumin in kidney. {ECO:0000269\|PubMed:14615060, ECO:0000269\|PubMed:15489223}.
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}.
Disease:		Periventricular nodular heterotopia 7 (PVNH7) [MIM:617201]: A form of periventricular nodular heterotopia, a disorder resulting from a defect in the pattern of neuronal migration in which ectopic collections of neurons lie along the lateral ventricles of the brain or just beneath, contiguously or in isolated patches. PVNH7 is an autosomal dominant disease characterized by delayed psychomotor development, intellectual disability, and seizures in some patients. Additional features include cleft palate and toe syndactyly. {ECO:0000269\|PubMed:27694961}. Note=The disease is caused by variants affecting the gene represented in this entry.
Sequence caution:		Sequence=BAA23711.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; Sequence=BAA23711.1; Type=Miscellaneous discrepancy; Note=Probable cloning artifact.; Evidence={ECO:0000305};