ADAM17 (ADAM metallopeptidase domain 17)

Note	ADAM17 belongs to the ADAM (a disintegrin and metalloprotease) family which is part of the adamalysin proteins. The activity and function of several membrane proteins is regulated by the proteolytic release of their ectodomains, a process known as shedding. About 2-4% of the proteins on the cell surface are affected by ectodomain shedding (Arribas and Massague, 1995). Since there are several of functionally and structurally diverse substrates, ADAMs are involved in various cellular processes. They take part in the regulation of cell adhesion, migration, development and signalling and are also implicated in pathologic conditions such as inflammation and cancer. The consequences of ectodomain shedding can vary, depending on the function of the substrate protein. Membrane-bound precursor proteins can be released by ADAMs as mature active molecules, for example ligands of the EGF receptor or cytokines like TNFa (Peschon et al., 1998; Blobel, 2005). Receptors, for example ErbB2 and ErbB4, can also be cleaved by ADAMs and thus become inactive or may still function as soluble decoy receptors (Molina et al., 2001; Vecchi et al., 1998). Contrariwise, receptors like Notch require proteolytic cleavage to generate intracellular signalling fragments that act as transcription factors after translocation to the nucleus. In this case ectodomain shedding is the prerequisite for regulated intramembrane proteolysis (RIP) mediated by intramembrane cleaving enzymes (Pan and Rubin, 1997; Brou et al., 2000).
	The structure of "a disintegrin and metalloproteases" consists of a N-terminal prodomain (aa 1-214) followed by a metalloprotease domain (aa 223-477), a disintegrin domain (aa 484-560) with a cystein-rich region, an epidermal growth factor-like domain (EGF) (aa 571-602), a transmembrane domain (TM) (aa 672-694) and a cytoplasmic tail (aa 695-824) (Arribas and Esselens, 2009 - modified). Amino acid specifications according to Pubmed graphics for ADAM17 (NP_003174.3).
Description	The preproform of ADAM17 contains 824 amino acids (134 kDa). After cleavage of the prodomain by furin or other proprotein convertases, the mature form has a predicted molecular weight of 98 kDa. The prodomain serves as a chaperone and keeps the enzyme in an inactive state during maturation in the trans-Golgi network (Schlöndorff et al., 2000). The catalytic domain contains the characteristic zinc binding motif (HEXXHXXGXXH) and three potential N-glycosylation sites. The disintegrin domain is discussed to be involved in regulation of the catalytic activity of ADAM17 (Li and Fan, 2004; Smith et al., 2002), but might also be involved in interaction with integrins and therefore mediate cell-cell adhesion or cell-matrix interaction. The cytoplasmic tail of ADAM17 was thought to be important in regulation of the enzyme activity because of its potential tyrosine phosphorylation site, but recent studies showed that overexpressed ADAM17 lacking its cytoplasmic domain was able to cleave TNFalpha upon phorbolester stimulation (Reddy et al., 2000; Horiuchi et al., 2007). The transmembrane domain might play a role in regulation of ADAM activity as studies with ADAM-chimera with exchanged transmembrane domains and experiments with plasma membrane modulating stimuli indicate (Le Gall et al., 2010; Reiss et al., 2011).
Expression	ADAM17 is ubiquitously expressed in various tissues, for example in the brain, kidney, heart and skeletal muscles. The expression pattern changes during embryonic development and the adult life (Black et al., 1997).
Localisation	ADAM17 is a type I transmembrane protein, but only 10% of the total protein can be found in the plasma membrane on the cell surface (Schlöndorff et al., 2000). Most of the protein is localised in the endoplasmic reticulum and trans-Golgi network. It is suggested that ADAM17 accumulates in cholesterol rich departments of the plasma membrane (lipid rafts) (Tellier et al., 2006).
Function	ADAM17 knockout mice display a severe phenotype that resembles mice lacking the epidermal growth factor receptor (EGFR) or one of its ligands (TGFalpha, HB-EGF or amphiregulin). Perinatal mortality is probably due to defects in heart development. Because of their catalytic and their disintegrin domain, ADAMs can have both adhesive and proteolytic functions. ADAM17 is best studied for its proteolytic properties and cleaves its substrates in the juxtamembrane region. The proteins processed by ADAM17 have different functions and therefore proteolytic processing can either activate or abrogate processes. For example both receptors and ligands can be cleaved, thus signalling can be either initiated or stopped by ADAM17.
Homology	Homologs of the human ADAM17 are found in various species ranging from other mammalians to primitive chordates like zebrafish. See table 1 for results of NCBI-Blast/blastp with human ADAM17 (NP_003174.3) as query sequence. Its closest relative in the family of human ADAM metalloproteases is ADAM10 (NP_001101.1), but there is only less than 30% amino acid sequence identity according to NCBI-Blast (blastp). Species Accession # identity to human ADAM17 similarity to human ADAM17 Sus scrofa NP_001093396.1 92% 97% Mus musculus NP_033745.4 92% 96% Rattus norwegicus NP_064702.1 92% 96% Gallus gallus NP_001008682.1 77% 87% Xenopus laevis NP_001089130.1 73% 85% Danio rerio NP_955967.1 61% 74% Drosophila melanogaster NP_733334.1 42% 59%

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