UniProt functional annotation for Q9HAU4



	UniProt functional annotation for Q9HAU4

UniProt code: Q9HAU4.

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 (PubMed:11016919). Interacts with SMAD7 to trigger SMAD7-mediated transforming growth factor beta/TGF-beta receptor ubiquitin-dependent degradation, thereby downregulating TGF-beta signaling (PubMed:11163210, PubMed:12717440). In addition, interaction with SMAD7 activates autocatalytic degradation, which is prevented by interaction with AIMP1 (PubMed:18448069). Also forms a stable complex with TGF-beta receptor-mediated phosphorylated SMAD1, SMAD2 and SMAD3, and targets SMAD1 and SMAD2 for ubiquitination and proteasome-mediated degradation (PubMed:11016919, PubMed:11158580, PubMed:11389444). SMAD2 may recruit substrates, such as SNON, for ubiquitin-dependent degradation (PubMed:11389444). Negatively regulates TGFB1-induced epithelial- mesenchymal transition and myofibroblast differentiation (PubMed:30696809). {ECO:0000269|PubMed:11016919, ECO:0000269|PubMed:11158580, ECO:0000269|PubMed:11163210, ECO:0000269|PubMed:11389444, ECO:0000269|PubMed:12717440, ECO:0000269|PubMed:18448069, ECO:0000269|PubMed:30696809}.

Function: (Microbial infection) In case of filoviruses Ebola/EBOV and Marburg/MARV infection, the complex formed by viral matrix protein VP40 and SMURF2 facilitates virus budding. {ECO:0000269|PubMed:33673144}.

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:0000269|PubMed:11016919};

Activity regulation: Activated by NDFIP1- and NDFIP2-binding. {ECO:0000269|PubMed:19343052}.

Pathway: Protein modification; protein ubiquitination.

Subunit: Interacts (via WW domains) with SMAD1 (PubMed:11158580). Interacts (via WW domains) with SMAD2 (via PY-motif) (PubMed:11158580, PubMed:11389444). Interacts (via WW domains) with SMAD3 (via PY-motif) (PubMed:11158580, PubMed:11389444). Interacts with SMAD6 (PubMed:11158580). Interacts with SMAD7 (via PY-motif) and TGFBR1; SMAD7 recruits SMURF2 to the TGF-beta receptor and regulates its degradation (PubMed:11163210, PubMed:11158580, PubMed:33673144, PubMed:16061177, PubMed:16641086). Does not interact with SMAD4; SMAD4 lacks a PY-motif (PubMed:11158580). Interacts with AIMP1 (PubMed:18448069). Interacts with SNON (PubMed:11389444). Interacts with STAMBP and RNF11 (PubMed:14562029, PubMed:14755250). May interact with NDFIP1 and NDFIP2; this interaction induces the E3 ubiquitin- protein ligase activity. Interacts with TTC3 (Probable). {ECO:0000269|PubMed:11158580, ECO:0000269|PubMed:11163210, ECO:0000269|PubMed:11389444, ECO:0000269|PubMed:14562029, ECO:0000269|PubMed:14755250, ECO:0000269|PubMed:16061177, ECO:0000269|PubMed:16641086, ECO:0000269|PubMed:18448069, ECO:0000269|PubMed:33673144, ECO:0000305|PubMed:30696809}.

Subunit: (Microbial infection) Interacts (via WW domains) with EBOV and MARV VP40 (via PPXY motif); the interaction facilitates VP40 virus-like particle budding. {ECO:0000269|PubMed:33673144}.

Subcellular location: Nucleus {ECO:0000269|PubMed:12717440}. Cytoplasm {ECO:0000269|PubMed:12717440}. Cell membrane {ECO:0000269|PubMed:12717440}. Membrane raft {ECO:0000269|PubMed:12717440}. Note=Cytoplasmic in the presence of SMAD7. Colocalizes with CAV1, SMAD7 and TGF-beta receptor in membrane rafts.

Tissue specificity: Widely expressed.

Domain: The second and third WW domains are responsible for interaction with the PY-motif of R-SMAD (SMAD1, SMAD2 and SMAD3).

Domain: The C2 domain is involved in autoinhibition of the catalytic activity by interacting with the HECT domain.

Domain: (Microbial infection) The WW domains mediate binding with matrix protein VP40. {ECO:0000269|PubMed:33673144}.

Ptm: Auto-ubiquitinated and ubiquitinated in the presence of RNF11 and UBE2D1 (PubMed:19343052, PubMed:30696809). Ubiquitinated by the SCF(FBXL15) complex and TTC3, leading to its degradation by the proteasome (PubMed:21572392, PubMed:30696809). {ECO:0000269|PubMed:19343052, ECO:0000269|PubMed:21572392, ECO:0000269|PubMed:30696809}.

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 (PubMed:11016919). Interacts with SMAD7 to trigger SMAD7-mediated transforming growth factor beta/TGF-beta receptor ubiquitin-dependent degradation, thereby downregulating TGF-beta signaling (PubMed:11163210, PubMed:12717440). In addition, interaction with SMAD7 activates autocatalytic degradation, which is prevented by interaction with AIMP1 (PubMed:18448069). Also forms a stable complex with TGF-beta receptor-mediated phosphorylated SMAD1, SMAD2 and SMAD3, and targets SMAD1 and SMAD2 for ubiquitination and proteasome-mediated degradation (PubMed:11016919, PubMed:11158580, PubMed:11389444). SMAD2 may recruit substrates, such as SNON, for ubiquitin-dependent degradation (PubMed:11389444). Negatively regulates TGFB1-induced epithelial- mesenchymal transition and myofibroblast differentiation (PubMed:30696809). {ECO:0000269\|PubMed:11016919, ECO:0000269\|PubMed:11158580, ECO:0000269\|PubMed:11163210, ECO:0000269\|PubMed:11389444, ECO:0000269\|PubMed:12717440, ECO:0000269\|PubMed:18448069, ECO:0000269\|PubMed:30696809}.



Function:		(Microbial infection) In case of filoviruses Ebola/EBOV and Marburg/MARV infection, the complex formed by viral matrix protein VP40 and SMURF2 facilitates virus budding. {ECO:0000269\|PubMed:33673144}.


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:0000269\|PubMed:11016919};
Activity regulation:		Activated by NDFIP1- and NDFIP2-binding. {ECO:0000269\|PubMed:19343052}.
Pathway:		Protein modification; protein ubiquitination.
Subunit:		Interacts (via WW domains) with SMAD1 (PubMed:11158580). Interacts (via WW domains) with SMAD2 (via PY-motif) (PubMed:11158580, PubMed:11389444). Interacts (via WW domains) with SMAD3 (via PY-motif) (PubMed:11158580, PubMed:11389444). Interacts with SMAD6 (PubMed:11158580). Interacts with SMAD7 (via PY-motif) and TGFBR1; SMAD7 recruits SMURF2 to the TGF-beta receptor and regulates its degradation (PubMed:11163210, PubMed:11158580, PubMed:33673144, PubMed:16061177, PubMed:16641086). Does not interact with SMAD4; SMAD4 lacks a PY-motif (PubMed:11158580). Interacts with AIMP1 (PubMed:18448069). Interacts with SNON (PubMed:11389444). Interacts with STAMBP and RNF11 (PubMed:14562029, PubMed:14755250). May interact with NDFIP1 and NDFIP2; this interaction induces the E3 ubiquitin- protein ligase activity. Interacts with TTC3 (Probable). {ECO:0000269\|PubMed:11158580, ECO:0000269\|PubMed:11163210, ECO:0000269\|PubMed:11389444, ECO:0000269\|PubMed:14562029, ECO:0000269\|PubMed:14755250, ECO:0000269\|PubMed:16061177, ECO:0000269\|PubMed:16641086, ECO:0000269\|PubMed:18448069, ECO:0000269\|PubMed:33673144, ECO:0000305\|PubMed:30696809}.
Subunit:		(Microbial infection) Interacts (via WW domains) with EBOV and MARV VP40 (via PPXY motif); the interaction facilitates VP40 virus-like particle budding. {ECO:0000269\|PubMed:33673144}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:12717440}. Cytoplasm {ECO:0000269\|PubMed:12717440}. Cell membrane {ECO:0000269\|PubMed:12717440}. Membrane raft {ECO:0000269\|PubMed:12717440}. Note=Cytoplasmic in the presence of SMAD7. Colocalizes with CAV1, SMAD7 and TGF-beta receptor in membrane rafts.
Tissue specificity:		Widely expressed.
Domain:		The second and third WW domains are responsible for interaction with the PY-motif of R-SMAD (SMAD1, SMAD2 and SMAD3).
Domain:		The C2 domain is involved in autoinhibition of the catalytic activity by interacting with the HECT domain.
Domain:		(Microbial infection) The WW domains mediate binding with matrix protein VP40. {ECO:0000269\|PubMed:33673144}.
Ptm:		Auto-ubiquitinated and ubiquitinated in the presence of RNF11 and UBE2D1 (PubMed:19343052, PubMed:30696809). Ubiquitinated by the SCF(FBXL15) complex and TTC3, leading to its degradation by the proteasome (PubMed:21572392, PubMed:30696809). {ECO:0000269\|PubMed:19343052, ECO:0000269\|PubMed:21572392, ECO:0000269\|PubMed:30696809}.