UniProt functional annotation for P78536



	UniProt functional annotation for P78536

UniProt code: P78536.

Organism: Homo sapiens (Human).

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

Function: Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form (PubMed:9034191). Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface (PubMed:20592283). Responsible for the proteolytic release of several other cell-surface proteins, including p75 TNF-receptor, interleukin 1 receptor type II, p55 TNF-receptor, transforming growth factor-alpha, L-selectin, growth hormone receptor, MUC1 and the amyloid precursor protein (PubMed:12441351). Acts as an activator of Notch pathway by mediating cleavage of Notch, generating the membrane-associated intermediate fragment called Notch extracellular truncation (NEXT) (PubMed:24226769). Plays a role in the proteolytic processing of ACE2 (PubMed:24227843). Plays a role in hemostasis through shedding of GP1BA, the platelet glycoprotein Ib alpha chain (By similarity). Mediates the proteolytic cleavage of LAG3, leading to release the secreted form of LAG3 (By similarity). Mediates the proteolytic cleavage of IL6R, leading to the release of secreted form of IL6R (PubMed:26876177, PubMed:28060820). {ECO:0000250|UniProtKB:Q9Z0F8, ECO:0000269|PubMed:12441351, ECO:0000269|PubMed:20592283, ECO:0000269|PubMed:24226769, ECO:0000269|PubMed:24227843, ECO:0000269|PubMed:26876177, ECO:0000269|PubMed:28060820, ECO:0000269|PubMed:9034191}.

Catalytic activity: Reaction=Narrow endopeptidase specificity. Cleaves Pro-Leu-Ala-Gln- Ala-|-Val-Arg-Ser-Ser-Ser in the membrane-bound, 26-kDa form of tumor necrosis factor alpha (TNF-alpha). Similarly cleaves other membrane- anchored, cell-surface proteins to 'shed' the extracellular domains.; EC=3.4.24.86; Evidence={ECO:0000269|PubMed:12441351, ECO:0000269|PubMed:20592283, ECO:0000269|PubMed:24227843};

Cofactor: Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269|PubMed:9520379}; Note=Binds 1 zinc ion per subunit. {ECO:0000269|PubMed:9520379};

Subunit: Interacts with MAD2L1, MAPK14 and MUC1 (PubMed:12441351, PubMed:20188673). Interacts with iRhom1/RHBDF1 and iRhom2/RHBDF2 (PubMed:29897333). Interacts with FRMD8 via its interaction with iRhom1/RHBDF1 and iRhom2/RHBDF2 (PubMed:29897333). {ECO:0000269|PubMed:12441351, ECO:0000269|PubMed:20188673, ECO:0000269|PubMed:29897333}.

Subcellular location: Membrane; Single-pass type I membrane protein.

Tissue specificity: Ubiquitously expressed. Expressed at highest levels in adult heart, placenta, skeletal muscle, pancreas, spleen, thymus, prostate, testes, ovary and small intestine, and in fetal brain, lung, liver and kidney.

Induction: In arthritis-affected cartilage.

Domain: Must be membrane anchored to cleave the different substrates. The cytoplasmic domain is not required for the this activity. Only the catalytic domain is essential to shed TNF and p75 TNFR (By similarity). {ECO:0000250}.

Domain: The conserved cysteine present in the cysteine-switch motif binds the catalytic zinc ion, thus inhibiting the enzyme. The dissociation of the cysteine from the zinc ion upon the activation- peptide release activates the enzyme.

Ptm: The precursor is cleaved by a furin endopeptidase. {ECO:0000250}.

Ptm: Phosphorylated. Stimulation by growth factor or phorbol 12- myristate 13-acetate induces phosphorylation of Ser-819 but decreases phosphorylation of Ser-791. Phosphorylation at THR-735 by MAPK14 is required for ADAM17-mediated ectodomain shedding. {ECO:0000269|PubMed:12058067, ECO:0000269|PubMed:12621058, ECO:0000269|PubMed:20188673}.

Disease: Inflammatory skin and bowel disease, neonatal, 1 (NISBD1) [MIM:614328]: A disorder characterized by inflammatory features with neonatal onset, involving the skin, hair, and gut. The skin lesions involve perioral and perianal erythema, psoriasiform erythroderma, with flares of erythema, scaling, and widespread pustules. Gastrointestinal symptoms include malabsorptive diarrhea that is exacerbated by intercurrent gastrointestinal infections. The hair is short or broken, and the eyelashes and eyebrows are wiry and disorganized. {ECO:0000269|PubMed:22010916}. Note=The disease is caused by variants affecting the gene represented in this entry.

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:		Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form (PubMed:9034191). Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface (PubMed:20592283). Responsible for the proteolytic release of several other cell-surface proteins, including p75 TNF-receptor, interleukin 1 receptor type II, p55 TNF-receptor, transforming growth factor-alpha, L-selectin, growth hormone receptor, MUC1 and the amyloid precursor protein (PubMed:12441351). Acts as an activator of Notch pathway by mediating cleavage of Notch, generating the membrane-associated intermediate fragment called Notch extracellular truncation (NEXT) (PubMed:24226769). Plays a role in the proteolytic processing of ACE2 (PubMed:24227843). Plays a role in hemostasis through shedding of GP1BA, the platelet glycoprotein Ib alpha chain (By similarity). Mediates the proteolytic cleavage of LAG3, leading to release the secreted form of LAG3 (By similarity). Mediates the proteolytic cleavage of IL6R, leading to the release of secreted form of IL6R (PubMed:26876177, PubMed:28060820). {ECO:0000250\|UniProtKB:Q9Z0F8, ECO:0000269\|PubMed:12441351, ECO:0000269\|PubMed:20592283, ECO:0000269\|PubMed:24226769, ECO:0000269\|PubMed:24227843, ECO:0000269\|PubMed:26876177, ECO:0000269\|PubMed:28060820, ECO:0000269\|PubMed:9034191}.


Catalytic activity:		Reaction=Narrow endopeptidase specificity. Cleaves Pro-Leu-Ala-Gln- Ala-\|-Val-Arg-Ser-Ser-Ser in the membrane-bound, 26-kDa form of tumor necrosis factor alpha (TNF-alpha). Similarly cleaves other membrane- anchored, cell-surface proteins to 'shed' the extracellular domains.; EC=3.4.24.86; Evidence={ECO:0000269\|PubMed:12441351, ECO:0000269\|PubMed:20592283, ECO:0000269\|PubMed:24227843};
Cofactor:		Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269\|PubMed:9520379}; Note=Binds 1 zinc ion per subunit. {ECO:0000269\|PubMed:9520379};
Subunit:		Interacts with MAD2L1, MAPK14 and MUC1 (PubMed:12441351, PubMed:20188673). Interacts with iRhom1/RHBDF1 and iRhom2/RHBDF2 (PubMed:29897333). Interacts with FRMD8 via its interaction with iRhom1/RHBDF1 and iRhom2/RHBDF2 (PubMed:29897333). {ECO:0000269\|PubMed:12441351, ECO:0000269\|PubMed:20188673, ECO:0000269\|PubMed:29897333}.
Subcellular location:		Membrane; Single-pass type I membrane protein.
Tissue specificity:		Ubiquitously expressed. Expressed at highest levels in adult heart, placenta, skeletal muscle, pancreas, spleen, thymus, prostate, testes, ovary and small intestine, and in fetal brain, lung, liver and kidney.
Induction:		In arthritis-affected cartilage.
Domain:		Must be membrane anchored to cleave the different substrates. The cytoplasmic domain is not required for the this activity. Only the catalytic domain is essential to shed TNF and p75 TNFR (By similarity). {ECO:0000250}.
Domain:		The conserved cysteine present in the cysteine-switch motif binds the catalytic zinc ion, thus inhibiting the enzyme. The dissociation of the cysteine from the zinc ion upon the activation- peptide release activates the enzyme.
Ptm:		The precursor is cleaved by a furin endopeptidase. {ECO:0000250}.
Ptm:		Phosphorylated. Stimulation by growth factor or phorbol 12- myristate 13-acetate induces phosphorylation of Ser-819 but decreases phosphorylation of Ser-791. Phosphorylation at THR-735 by MAPK14 is required for ADAM17-mediated ectodomain shedding. {ECO:0000269\|PubMed:12058067, ECO:0000269\|PubMed:12621058, ECO:0000269\|PubMed:20188673}.
Disease:		Inflammatory skin and bowel disease, neonatal, 1 (NISBD1) [MIM:614328]: A disorder characterized by inflammatory features with neonatal onset, involving the skin, hair, and gut. The skin lesions involve perioral and perianal erythema, psoriasiform erythroderma, with flares of erythema, scaling, and widespread pustules. Gastrointestinal symptoms include malabsorptive diarrhea that is exacerbated by intercurrent gastrointestinal infections. The hair is short or broken, and the eyelashes and eyebrows are wiry and disorganized. {ECO:0000269\|PubMed:22010916}. Note=The disease is caused by variants affecting the gene represented in this entry.