Description: Homo sapiens ADAM metallopeptidase domain 17 (ADAM17), mRNA. RefSeq Summary (NM_003183): This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biologic processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. The encoded preproprotein is proteolytically processed to generate the mature protease. The encoded protease functions in the ectodomain shedding of tumor necrosis factor-alpha, in which soluble tumor necrosis factor-alpha is released from the membrane-bound precursor. This protease also functions in the processing of numerous other substrates, including cell adhesion proteins, cytokine and growth factor receptors and epidermal growth factor (EGF) receptor ligands. The encoded protein also plays a prominent role in the activation of the Notch signaling pathway. Elevated expression of this gene has been observed in specific cell types derived from psoriasis, rheumatoid arthritis, multiple sclerosis and Crohn's disease patients, suggesting that the encoded protein may play a role in autoimmune disease. [provided by RefSeq, Feb 2016]. Sequence Note: This RefSeq record was created from transcript and genomic sequence data to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on transcript alignments. Transcript (Including UTRs) Position: hg19 chr2:9,629,411-9,695,917 Size: 66,507 Total Exon Count: 18 Strand: - Coding Region Position: hg19 chr2:9,630,306-9,695,734 Size: 65,429 Coding Exon Count: 18
ID:ADA17_HUMAN DESCRIPTION: RecName: Full=Disintegrin and metalloproteinase domain-containing protein 17; Short=ADAM 17; EC=3.4.24.86; AltName: Full=Snake venom-like protease; AltName: Full=TNF-alpha convertase; AltName: Full=TNF-alpha-converting enzyme; AltName: CD_antigen=CD156b; Flags: Precursor; FUNCTION: Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface. 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. Also involved in the activation of Notch pathway (By similarity). CATALYTIC ACTIVITY: 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. COFACTOR: Binds 1 zinc ion per subunit. SUBUNIT: Interacts with MAD2L1, MAPK14 and MUC1. INTERACTION: Q13257:MAD2L1; NbExp=3; IntAct=EBI-78188, EBI-78203; 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). 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 (By similarity). 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. DISEASE: Defects in ADAM17 are a cause of neonatal inflammatory skin and bowel disease (NISBD) [MIM:614328]. NISBD is 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. SIMILARITY: Contains 1 disintegrin domain. SIMILARITY: Contains 1 peptidase M12B domain. WEB RESOURCE: Name=Wikipedia; Note=Tumor necrosis factor alpha- converting enzyme entry; URL="http://en.wikipedia.org/wiki/Tumor_Necrosis_Factor_Alpha_Converting_Enzyme";
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Genetic Association Studies of Complex Diseases and Disorders
Genetic Association Database (archive): ADAM17 CDC HuGE Published Literature: ADAM17 Positive Disease Associations: Heart Rate Related Studies:
Heart Rate Tuomo Rankinen et al. Journal of applied physiology (Bethesda, Md. : 1985) 2012, Heritability of submaximal exercise heart rate response to exercise training is accounted for by nine SNPs., Journal of applied physiology (Bethesda, Md. : 1985).
[PubMed 22174390]
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P78536
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
KEGG - Kyoto Encyclopedia of Genes and Genomes hsa04330 - Notch signaling pathway hsa05010 - Alzheimer's disease hsa05120 - Epithelial cell signaling in Helicobacter pylori infection
BioCarta from NCI Cancer Genome Anatomy Project h_notchpathway - Proteolysis and Signaling Pathway of Notch h_ps1Pathway - Presenilin action in Notch and Wnt signaling h_erbB4pathway - g-Secretase mediated ErbB4 Signaling Pathway
Reactome (by CSHL, EBI, and GO)
Protein P78536 (Reactome details) participates in the following event(s):
R-HSA-1168777 Metalloprotease cleavage of GHR R-NUL-5362792 Shh is released from the plasma membrane by ADAM17-mediated cleavage R-HSA-5362793 Hh-Np is cleaved by ADAM17 to promote ligand shedding R-HSA-193679 alpha-secretase cleaves the p75NTR extracellular domain R-HSA-1251992 Cleavage of P-ERBB4jmA isoforms by ADAM17 R-NUL-2063915 ADAM17 cleaves Notch1 at S2 R-HSA-3371385 TNF-alpha is cleaved by ADAM17 (TACE) R-HSA-2168960 Collagen type XVII ectodomain shedding R-HSA-177946 Pro-EGF is cleaved to form mature EGF R-HSA-157632 Complex of NOTCH1 with its ligand is cleaved to produce NEXT1 R-HSA-2220944 ADAM10/17 cleaves ligand-bound NOTCH1 PEST domain mutants to produce NEXT1 PEST domain mutants R-HSA-2220976 NOTCH1 HD+PEST domain mutants are cleaved by ADAM10/17 irrespective of ligand binding R-HSA-2666278 NOTCH1 t(7;9)(NOTCH1:M1580_K2555) is cleaved to produce NEXT1 R-HSA-2730752 NOTCH1 HD domain mutants are cleaved to produce NEXT1 irrespective of ligand binding R-HSA-982772 Growth hormone receptor signaling R-HSA-5362798 Release of Hh-Np from the secreting cell R-HSA-193692 Regulated proteolysis of p75NTR R-HSA-1251985 Nuclear signaling by ERBB4 R-HSA-75893 TNF signaling R-HSA-1442490 Collagen degradation R-HSA-1280215 Cytokine Signaling in Immune system R-HSA-5358346 Hedgehog ligand biogenesis R-HSA-193704 p75 NTR receptor-mediated signalling R-HSA-1236394 Signaling by ERBB4 R-HSA-73887 Death Receptor Signalling R-HSA-177929 Signaling by EGFR R-HSA-1474228 Degradation of the extracellular matrix R-HSA-156988 Receptor-ligand binding initiates the second proteolytic cleavage of Notch receptor R-HSA-2122948 Activated NOTCH1 Transmits Signal to the Nucleus R-HSA-2644606 Constitutive Signaling by NOTCH1 PEST Domain Mutants R-HSA-2894862 Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants R-HSA-2660826 Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant R-HSA-2691232 Constitutive Signaling by NOTCH1 HD Domain Mutants R-HSA-168256 Immune System R-HSA-5358351 Signaling by Hedgehog R-HSA-9006934 Signaling by Receptor Tyrosine Kinases R-HSA-162582 Signal Transduction R-HSA-1474244 Extracellular matrix organization R-HSA-1980143 Signaling by NOTCH1 R-HSA-2644602 Signaling by NOTCH1 PEST Domain Mutants in Cancer R-HSA-2894858 Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer R-HSA-2660825 Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant R-HSA-2691230 Signaling by NOTCH1 HD Domain Mutants in Cancer R-HSA-157118 Signaling by NOTCH R-HSA-2644603 Signaling by NOTCH1 in Cancer R-HSA-5663202 Diseases of signal transduction R-HSA-1643685 Disease