UniProt functional annotation for Q6ZNA4



	UniProt functional annotation for Q6ZNA4

UniProt code: Q6ZNA4.

Organism: Homo sapiens (Human).

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

Function: E3 ubiquitin-protein ligase (PubMed:26656854). Required for mesoderm patterning during embryonic development (By similarity). Acts as an enhancer of the transcriptional responses of the SMAD2/SMAD3 effectors, which are activated downstream of BMP (PubMed:14657019, PubMed:16601693). Acts by mediating ubiquitination and degradation of SMAD inhibitors such as SMAD7, inducing their proteasomal degradation and thereby enhancing the transcriptional activity of TGF-beta and BMP (PubMed:14657019, PubMed:16601693). In addition to enhance transcription of SMAD2/SMAD3 effectors, also regulates their turnover by mediating their ubiquitination and subsequent degradation, coupling their activation with degradation, thereby ensuring that only effectors 'in use' are degraded (By similarity). Activates SMAD3/SMAD4-dependent transcription by triggering signal-induced degradation of SNON isoform of SKIL (PubMed:17591695). Associates with UBE2D2 as an E2 enzyme (PubMed:22411132). Specifically binds polysumoylated chains via SUMO interaction motifs (SIMs) and mediates ubiquitination of sumoylated substrates (PubMed:23751493). Catalyzes 'Lys-63'-linked ubiquitination of sumoylated XPC in response to UV irradiation, promoting nucleotide excision repair (PubMed:23751493). Mediates ubiquitination and degradation of sumoylated PML (By similarity). The regulation of the BMP-SMAD signaling is however independent of sumoylation and is not dependent of SUMO interaction motifs (SIMs) (By similarity). {ECO:0000250|UniProtKB:Q99ML9, ECO:0000269|PubMed:14657019, ECO:0000269|PubMed:16601693, ECO:0000269|PubMed:17591695, ECO:0000269|PubMed:22411132, ECO:0000269|PubMed:23751493, ECO:0000269|PubMed:26656854}.

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=2.3.2.27; Evidence={ECO:0000269|PubMed:23751493};

Activity regulation: Binds free ubiquitin non-covalently via its RING- type zinc finger. Ubiquitin-binding leads to enhance the E3 ubiquitin- protein ligase activity by stabilizing the ubiquitin-conjugating enzyme E2 (donor ubiquitin) in the 'closed' conformation and activating ubiquitin transfer. {ECO:0000250|UniProtKB:Q6ZSG1}.

Pathway: Protein modification; protein ubiquitination. {ECO:0000269|PubMed:14657019, ECO:0000269|PubMed:16601693, ECO:0000269|PubMed:17591695, ECO:0000269|PubMed:22411132, ECO:0000269|PubMed:23751493, ECO:0000269|PubMed:26656854}.

Subunit: Monomer (PubMed:26656854). Interacts with SMAD6, SMAD7, AXIN1, AXIN2 and SKIL isoform SNON (PubMed:16601693, PubMed:17591695). Interacts with (phosphorylated) SMAD2 and SMAD3 (By similarity). Part of a complex containing RNF111, AXIN1 and SMAD7 (PubMed:16601693). Interacts (via SIM domains) with SUMO1 and SUMO2 (PubMed:23086935). {ECO:0000250|UniProtKB:Q99ML9, ECO:0000269|PubMed:16601693, ECO:0000269|PubMed:17591695, ECO:0000269|PubMed:23086935, ECO:0000269|PubMed:26656854}.

Subcellular location: Nucleus {ECO:0000269|PubMed:16601693, ECO:0000269|PubMed:23751493}. Cytoplasm {ECO:0000269|PubMed:16601693}. Nucleus, PML body {ECO:0000250|UniProtKB:Q99ML9}. Note=Upon TGF-beta treatment, translocates from nucleus to cytosol. {ECO:0000269|PubMed:16601693}.

Tissue specificity: Broadly expressed. {ECO:0000269|PubMed:14657019}.

Domain: The SUMO interaction motifs (SIMs) mediates the binding to polysumoylated substrate. {ECO:0000269|PubMed:23086935, ECO:0000269|PubMed:23751493}.

Domain: The RING-type zinc finger mediates the E3 ubiquitin-protein ligase activity and binds directly to free ubiquitin (PubMed:26656854). Non-covalent ubiquitin-binding stabilizes the ubiquitin-conjugating enzyme E2 (donor ubiquitin) in the 'closed' conformation and stimulates ubiquitin transfer (By similarity). {ECO:0000250|UniProtKB:Q6ZSG1, ECO:0000305|PubMed:26656854}.

Similarity: Belongs to the Arkadia family. {ECO:0000305}.

Sequence caution: Sequence=AAH10369.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; Sequence=BAC04531.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; Sequence=BAD18633.1; Type=Erroneous initiation; Note=Truncated N-terminus.; 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 (PubMed:26656854). Required for mesoderm patterning during embryonic development (By similarity). Acts as an enhancer of the transcriptional responses of the SMAD2/SMAD3 effectors, which are activated downstream of BMP (PubMed:14657019, PubMed:16601693). Acts by mediating ubiquitination and degradation of SMAD inhibitors such as SMAD7, inducing their proteasomal degradation and thereby enhancing the transcriptional activity of TGF-beta and BMP (PubMed:14657019, PubMed:16601693). In addition to enhance transcription of SMAD2/SMAD3 effectors, also regulates their turnover by mediating their ubiquitination and subsequent degradation, coupling their activation with degradation, thereby ensuring that only effectors 'in use' are degraded (By similarity). Activates SMAD3/SMAD4-dependent transcription by triggering signal-induced degradation of SNON isoform of SKIL (PubMed:17591695). Associates with UBE2D2 as an E2 enzyme (PubMed:22411132). Specifically binds polysumoylated chains via SUMO interaction motifs (SIMs) and mediates ubiquitination of sumoylated substrates (PubMed:23751493). Catalyzes 'Lys-63'-linked ubiquitination of sumoylated XPC in response to UV irradiation, promoting nucleotide excision repair (PubMed:23751493). Mediates ubiquitination and degradation of sumoylated PML (By similarity). The regulation of the BMP-SMAD signaling is however independent of sumoylation and is not dependent of SUMO interaction motifs (SIMs) (By similarity). {ECO:0000250\|UniProtKB:Q99ML9, ECO:0000269\|PubMed:14657019, ECO:0000269\|PubMed:16601693, ECO:0000269\|PubMed:17591695, ECO:0000269\|PubMed:22411132, ECO:0000269\|PubMed:23751493, ECO:0000269\|PubMed:26656854}.


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=2.3.2.27; Evidence={ECO:0000269\|PubMed:23751493};
Activity regulation:		Binds free ubiquitin non-covalently via its RING- type zinc finger. Ubiquitin-binding leads to enhance the E3 ubiquitin- protein ligase activity by stabilizing the ubiquitin-conjugating enzyme E2 (donor ubiquitin) in the 'closed' conformation and activating ubiquitin transfer. {ECO:0000250\|UniProtKB:Q6ZSG1}.
Pathway:		Protein modification; protein ubiquitination. {ECO:0000269\|PubMed:14657019, ECO:0000269\|PubMed:16601693, ECO:0000269\|PubMed:17591695, ECO:0000269\|PubMed:22411132, ECO:0000269\|PubMed:23751493, ECO:0000269\|PubMed:26656854}.
Subunit:		Monomer (PubMed:26656854). Interacts with SMAD6, SMAD7, AXIN1, AXIN2 and SKIL isoform SNON (PubMed:16601693, PubMed:17591695). Interacts with (phosphorylated) SMAD2 and SMAD3 (By similarity). Part of a complex containing RNF111, AXIN1 and SMAD7 (PubMed:16601693). Interacts (via SIM domains) with SUMO1 and SUMO2 (PubMed:23086935). {ECO:0000250\|UniProtKB:Q99ML9, ECO:0000269\|PubMed:16601693, ECO:0000269\|PubMed:17591695, ECO:0000269\|PubMed:23086935, ECO:0000269\|PubMed:26656854}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:16601693, ECO:0000269\|PubMed:23751493}. Cytoplasm {ECO:0000269\|PubMed:16601693}. Nucleus, PML body {ECO:0000250\|UniProtKB:Q99ML9}. Note=Upon TGF-beta treatment, translocates from nucleus to cytosol. {ECO:0000269\|PubMed:16601693}.
Tissue specificity:		Broadly expressed. {ECO:0000269\|PubMed:14657019}.
Domain:		The SUMO interaction motifs (SIMs) mediates the binding to polysumoylated substrate. {ECO:0000269\|PubMed:23086935, ECO:0000269\|PubMed:23751493}.
Domain:		The RING-type zinc finger mediates the E3 ubiquitin-protein ligase activity and binds directly to free ubiquitin (PubMed:26656854). Non-covalent ubiquitin-binding stabilizes the ubiquitin-conjugating enzyme E2 (donor ubiquitin) in the 'closed' conformation and stimulates ubiquitin transfer (By similarity). {ECO:0000250\|UniProtKB:Q6ZSG1, ECO:0000305\|PubMed:26656854}.
Similarity:		Belongs to the Arkadia family. {ECO:0000305}.
Sequence caution:		Sequence=AAH10369.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; Sequence=BAC04531.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; Sequence=BAD18633.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};