Detail Information for IndEnz0002018704
IED ID IndEnz0002018704
Enzyme Type ID protease018704
Protein Name Disintegrin and metalloproteinase domain-containing protein 10
ADAM 10
EC 3.4.24.81
CDw156
Kuzbanian protein homolog
Mammalian disintegrin-metalloprotease
CD antigen CD156c
Gene Name ADAM10 KUZ MADM
Organism Homo sapiens (Human)
Taxonomic Lineage cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human)
Enzyme Sequence MVLLRVLILLLSWAAGMGGQYGNPLNKYIRHYEGLSYNVDSLHQKHQRAKRAVSHEDQFLRLDFHAHGRHFNLRMKRDTSLFSDEFKVETSNKVLDYDTSHIYTGHIYGEEGSFSHGSVIDGRFEGFIQTRGGTFYVEPAERYIKDRTLPFHSVIYHEDDINYPHKYGPQGGCADHSVFERMRKYQMTGVEEVTQIPQEEHAANGPELLRKKRTTSAEKNTCQLYIQTDHLFFKYYGTREAVIAQISSHVKAIDTIYQTTDFSGIRNISFMVKRIRINTTADEKDPTNPFRFPNIGVEKFLELNSEQNHDDYCLAYVFTDRDFDDGVLGLAWVGAPSGSSGGICEKSKLYSDGKKKSLNTGIITVQNYGSHVPPKVSHITFAHEVGHNFGSPHDSGTECTPGESKNLGQKENGNYIMYARATSGDKLNNNKFSLCSIRNISQVLEKKRNNCFVESGQPICGNGMVEQGEECDCGYSDQCKDECCFDANQPEGRKCKLKPGKQCSPSQGPCCTAQCAFKSKSEKCRDDSDCAREGICNGFTALCPASDPKPNFTDCNRHTQVCINGQCAGSICEKYGLEECTCASSDGKDDKELCHVCCMKKMDPSTCASTGSVQWSRHFSGRTITLQPGSPCNDFRGYCDVFMRCRLVDADGPLARLKKAIFSPELYENIAEWIVAHWWAVLLMGIALIMLMAGFIKICSVHTPSSNPKLPPPKPLPGTLKRRRPPQPIQQPQRQRPRESYQMGHMRR
Enzyme Length 748
Uniprot Accession Number O14672
Absorption
Active Site ACT_SITE 384; /evidence="ECO:0000269|PubMed:29224781, ECO:0000269|PubMed:29430990"
Activity Regulation ACTIVITY REGULATION: Catalytically inactive when the propeptide is intact and associated with the mature enzyme (By similarity). The disintegrin and cysteine-rich regions modulate access of substrates to exerts an inhibitory effect on the cleavage of ADAM10 substrates (PubMed:29224781). {ECO:0000250|UniProtKB:Q10741, ECO:0000269|PubMed:29224781}.
Binding Site
Calcium Binding
catalytic Activity CATALYTIC ACTIVITY: Reaction=Endopeptidase of broad specificity.; EC=3.4.24.81; Evidence={ECO:0000269|PubMed:11477090, ECO:0000269|PubMed:11786905, ECO:0000269|PubMed:12475894, ECO:0000269|PubMed:16239146, ECO:0000269|PubMed:17557115, ECO:0000269|PubMed:19114711, ECO:0000269|PubMed:20592283, ECO:0000269|PubMed:21288900, ECO:0000269|PubMed:26686862, ECO:0000269|PubMed:29224781, ECO:0000269|PubMed:29430990, ECO:0000305|PubMed:24990881};
DNA Binding
EC Number 3.4.24.81
Enzyme Function FUNCTION: Cleaves the membrane-bound precursor of TNF-alpha at '76-Ala-|-Val-77' to its mature soluble form. 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 heparin-binding epidermal growth-like factor, ephrin-A2, CD44, CDH2 and for constitutive and regulated alpha-secretase cleavage of amyloid precursor protein (APP) (PubMed:26686862, PubMed:11786905, PubMed:29224781). Contributes to the normal cleavage of the cellular prion protein (PubMed:11477090). Involved in the cleavage of the adhesion molecule L1 at the cell surface and in released membrane vesicles, suggesting a vesicle-based protease activity (PubMed:12475894). Controls also the proteolytic processing of Notch and mediates lateral inhibition during neurogenesis (By similarity). Responsible for the FasL ectodomain shedding and for the generation of the remnant ADAM10-processed FasL (FasL APL) transmembrane form (PubMed:17557115). Also cleaves the ectodomain of the integral membrane proteins CORIN and ITM2B (PubMed:19114711, PubMed:21288900). Mediates the proteolytic cleavage of LAG3, leading to release the secreted form of LAG3 (By similarity). Mediates the proteolytic cleavage of IL6R and IL11RA, leading to the release of secreted forms of IL6R and IL11RA (PubMed:26876177). Enhances the cleavage of CHL1 by BACE1 (By similarity). Cleaves NRCAM (By similarity). Cleaves TREM2, resulting in shedding of the TREM2 ectodomain (PubMed:24990881). Involved in the development and maturation of glomerular and coronary vasculature (By similarity). During development of the cochlear organ of Corti, promotes pillar cell separation by forming a ternary complex with CADH1 and EPHA4 and cleaving CADH1 at adherens junctions (By similarity). May regulate the EFNA5-EPHA3 signaling (PubMed:16239146). {ECO:0000250|UniProtKB:O35598, ECO:0000269|PubMed:11477090, ECO:0000269|PubMed:11786905, ECO:0000269|PubMed:12475894, ECO:0000269|PubMed:16239146, ECO:0000269|PubMed:17557115, ECO:0000269|PubMed:19114711, ECO:0000269|PubMed:20592283, ECO:0000269|PubMed:21288900, ECO:0000269|PubMed:24990881, ECO:0000269|PubMed:26686862, ECO:0000269|PubMed:26876177, ECO:0000269|PubMed:29224781}.; FUNCTION: (Microbial infection) Promotes the cytotoxic activity of S.aureus hly by binding to the toxin at zonula adherens and promoting formation of toxin pores. {ECO:0000269|PubMed:20624979, ECO:0000269|PubMed:30463011}.
Temperature Dependency
PH Dependency
Pathway
nucleotide Binding
Features Active site (1); Alternative sequence (1); Beta strand (19); Chain (1); Compositional bias (1); Disulfide bond (17); Domain (2); Glycosylation (4); Helix (14); Metal binding (4); Modified residue (1); Motif (3); Mutagenesis (1); Natural variant (5); Propeptide (1); Region (2); Sequence conflict (3); Signal peptide (1); Site (1); Topological domain (2); Transmembrane (1); Turn (6)
Keywords 3D-structure;Alternative splicing;Alzheimer disease;Amyloidosis;Cell junction;Cell membrane;Cell projection;Cleavage on pair of basic residues;Cytoplasm;Cytoplasmic vesicle;Direct protein sequencing;Disease variant;Disulfide bond;Glycoprotein;Golgi apparatus;Hydrolase;Membrane;Metal-binding;Metalloprotease;Neurodegeneration;Notch signaling pathway;Phosphoprotein;Protease;Reference proteome;SH3-binding;Signal;Transmembrane;Transmembrane helix;Zinc;Zymogen
Interact With P00519; P05067; P56817; P60033; P21926; P06241; Q13588; O75791; P62993; P08631; P06239; Q9BY11; Q9UNF0; Q9UKS6; Q99961; Q96RF0; P12931; O95859; Q8NG11; O95858; Q86UF1; P62079; P07947; P60033; O95859
Induction INDUCTION: In osteoarthritis affected-cartilage.
Subcellular Location SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:20624979, ECO:0000269|PubMed:23676497, ECO:0000269|PubMed:24990881, ECO:0000269|PubMed:26686862, ECO:0000269|PubMed:29430990, ECO:0000269|PubMed:30463011}; Single-pass type I membrane protein {ECO:0000305}. Golgi apparatus membrane {ECO:0000269|PubMed:12475894}; Single-pass type I membrane protein {ECO:0000305}. Cytoplasmic vesicle, clathrin-coated vesicle {ECO:0000269|PubMed:12475894}. Cell projection, axon {ECO:0000250|UniProtKB:O35598}. Cell projection, dendrite {ECO:0000250|UniProtKB:O35598}. Cell junction, adherens junction {ECO:0000269|PubMed:30463011}. Cytoplasm {ECO:0000269|PubMed:30463011}. Note=Is localized in the plasma membrane but is also expressed in the Golgi apparatus and in clathrin-coated vesicles derived likely from the Golgi (PubMed:12475894). During long term depression, it is recruited to the cell membrane by DLG1 (PubMed:23676497). The immature form is mainly located near cytoplasmic fibrillar structures, while the mature form is predominantly located at zonula adherens and the cell membrane (PubMed:30463011). The localization and clustering of mature ADAM10 to zonula adherens is regulated by AFDN, TSPAN33, PLEKHA7 and PDZD11 (PubMed:30463011). {ECO:0000269|PubMed:12475894, ECO:0000269|PubMed:23676497, ECO:0000269|PubMed:30463011}.
Modified Residue MOD_RES 719; /note="Phosphothreonine; by FAM20C"; /evidence="ECO:0000269|PubMed:26091039, ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569"
Post Translational Modification PTM: The precursor is cleaved by furin and PCSK7. {ECO:0000250|UniProtKB:Q10741}.
Signal Peptide SIGNAL 1..19; /evidence=ECO:0000255
Structure 3D X-ray crystallography (2)
Cross Reference PDB 6BDZ; 6BE6;
Mapped Pubmed ID 10097139; 10882063; 10958687; 10958785; 11839628; 12080182; 12354787; 12356719; 12438920; 12535668; 12568494; 12590602; 12629514; 12665519; 12730960; 12782344; 12815056; 12832423; 12960155; 14627705; 14636066; 14707550; 15182369; 15280425; 15300588; 15507448; 15905513; 15958533; 16054021; 16263114; 16390331; 16627989; 16648485; 16735514; 16738328; 16751190; 16806063; 16942750; 17170699; 17187903; 17290285; 17401372; 17699774; 17727679; 17895248; 17965014; 18074395; 18200054; 18215140; 1831692; 18355445; 18373975; 18381078; 18420943; 18434311; 18480749; 18514661; 18603587; 18642355; 18952609; 18971959; 18979631; 18981120; 19091752; 19144697; 19260824; 19278423; 19344981; 19357285; 19394555; 19426159; 19435795; 19541935; 19564338; 19587294; 19603142; 19632330; 19665015; 19667218; 19672558; 19704010; 19726682; 19783906; 19826051; 19865098; 19913121; 20059578; 20070888; 20136654; 20156974; 20195357; 20348102; 20371803; 20381196; 20443867; 20628086; 20676056; 20677014; 20711474; 20711500; 20814017; 20863729; 21103979; 21123580; 21171968; 21196064; 21259244; 21368228; 21402705; 21441465; 21569301; 21576249; 21625236; 21695060; 21804545; 21876729; 21956108; 21959176; 21969210; 22006996; 22065584; 22116825; 22167753; 22474035; 22572541; 22586143; 22613720; 22641052; 22658936; 22689693; 22770404; 22923171; 22933306; 22940630; 22940701; 23035126; 23124962; 23192951; 23289620; 23306532; 23416715; 23429442; 23460612; 23526433; 23546882; 23579328; 23650620; 23674691; 23720309; 23746173; 23773531; 23912592; 24055471; 24121505; 24130797; 24165480; 24189063; 24247244; 24286866; 24386293; 24518602; 24530397; 24548763; 24625754; 24662289; 24670536; 24725932; 24833351; 24842903; 24935471; 24952873; 24985126; 24998958; 25036101; 25124714; 25130545; 25155463; 25218471; 25253723; 25318895; 25323956; 25333745; 25349418; 25387128; 25429624; 25540428; 25609823; 25631235; 25654651; 25745808; 25796462; 25888255; 25933166; 26021209; 26071561; 26090866; 26182420; 26220620; 26244291; 26250527; 26266086; 26283728; 26296735; 26310711; 26325204; 26359498; 26422658; 26555131; 26704053; 26840909; 26863569; 26947053; 26986985; 27012683; 27043625; 27151651; 27237127; 27242325; 27259866; 27354212; 27503072; 27503326; 27517630; 27541285; 27546281; 27628319; 27818272; 27837433; 28184920; 28232483; 28292959; 28427048; 28449222; 28600292; 28611181; 28620033; 28624437; 28624438; 28656294; 28687716; 28739265; 28801670; 28814605; 28819788; 28982863; 29054606; 29152656; 29192958; 29253717; 29604594; 29630665; 29895129; 30275760; 30279425; 30391432; 30470613; 30599067; 30651596; 30661303; 30792527; 30833305; 30872401; 30926762; 30987833; 31026069; 31063986; 31165998; 31308029; 31370093; 31381863; 31387910; 31786854; 31796994; 31843015; 31953323; 32019490; 32111735; 32193206; 32363112; 32372373; 32715474; 32934081; 33051240; 33082206; 33129344; 33383559; 33416124; 33504031; 33526513; 33670873; 33731436; 33760683; 33800462; 34192661; 34390512; 34778975; 9244301;
Motif MOTIF 171..178; /note=Cysteine switch; /evidence=ECO:0000250; MOTIF 708..715; /note=SH3-binding; /evidence=ECO:0000255; MOTIF 722..728; /note=SH3-binding; /evidence=ECO:0000255
Gene Encoded By
Mass 84,142
Kinetics
Metal Binding METAL 173; /note="Zinc; in inhibited form"; /evidence="ECO:0000250|UniProtKB:P03956"; METAL 383; /note="Zinc; via tele nitrogen; catalytic"; /evidence="ECO:0000269|PubMed:24055016, ECO:0000269|PubMed:29224781, ECO:0007744|PDB:6BDZ, ECO:0007744|PDB:6BE6"; METAL 387; /note="Zinc; via tele nitrogen; catalytic"; /evidence="ECO:0000269|PubMed:29224781, ECO:0007744|PDB:6BE6"; METAL 393; /note="Zinc; via tele nitrogen; catalytic"; /evidence="ECO:0000269|PubMed:24055016, ECO:0000269|PubMed:29224781, ECO:0007744|PDB:6BDZ, ECO:0007744|PDB:6BE6"
Rhea ID
Cross Reference Brenda 3.4.24.81;