Summary for peptidase M12.215: ADAM15 peptidase

Summary Gene structure Alignment Tree Sequences Sequence features Distribution Literature Human EST Mouse EST Substrates Inhibitors

 

Names
MEROPS NameADAM15 peptidase
Other namesMDC15, metargidin
Name and HistoryADAM15 is a membrane-bound sheddase. It was initially named metargidin because of the presence of an RGD motif in the human sequence (Kratzschmar et al., 1996).
Domain architecture
MEROPS Classification
Classification Clan MA >> Subclan MA(M) >> Family M12 >> Subfamily B >> M12.215
HolotypeADAM15 peptidase (Homo sapiens), Uniprot accession Q13444 (peptidase unit: 209-414), MERNUM MER0002386
History Identifier created: MEROPS 3.02 (25 June 1998)
Activity
Catalytic typeMetallo
NC-IUBMBNot yet included in IUBMB recommendations.
Activity statushuman: active (Martin et al., 2002)
mouse: putative
SpecificityADAM15 either sheds the ectodomain of fibroblast growth factor receptor 2iiib or activates the sheddase responsible (Maretzky et al., 2009). Human ADAM15 has been shown to bind to integrins via its RGD motif (Nath et al., 1999).
Special substrateM-2055 (Dnp-Pro-beta-cyclohexyl-Ala-Gly-Cys(Me)-His-Ala-Lys(N-Me-Abz)-NH2) (Martin et al., 2002).
Inhibitor commentsInhibited by marimastat, TAPI-2, GM6001 and TIMP-3 (Maretzky et al., 2009).
StructureThe ADAM15 is a glycosylated, single-pass type I membrane protein. The sequence contains a propeptide, a metallopeptidase, a disintegrin and an ADAM-CR domain, a transmembrane region and a proline-rich cytoplasmic tail, and in humans the disintegrin domain contains an RGD motif (this is not present in orthologues from all species and is absent in the mouse protein). ADAM15 may exist in a heterodimer with a 56 kDa protein with which is immunoprecipitates (Kratzschmar et al., 1996).
Biological aspectsThe precursor is correctly processed by furin; processing occurs in a late Golgi compartment (Lum et al., 1998).
RNA splicingA splice variant, which has a different cytoplasmic tail containing an Src-binding site, is found in a human colonic cell line (Charrier et al., 2005) and breast cancer cells (Maretzky et al., 2009).
KnockoutA mouse knockout for the adam15 gene showed no apparent defects, but in a model for retinopathy, adam15-/- mice had a major reduction in neovascularization and tumours resulting from implanted melanomas were smaller (Nath et al., 1999).
Pharmaceutical relevanceThe ADAM15 gene is overexpressed in several human cancers (Kuefer et al., 2006) and has been implicated in pathological neovascularization (Nath et al., 1999) and prostate cancer metastasis. ADAM15 is also found in the macrophage-rich core lesions of atherosclerosis (Herren et al., 1997) and attenuates the progression of the disease in cholesterol-fed rabbits (Bultmann et al., 2011). ADAM15 on the surface of endothelial cells binds platelets via a surface integrin, and bound platelets are activated and can lead to clot development making ADAM15 a potential target for cardiovascular disease (Herren et al., 2001). Increased expression of ADAM15 is seen in rheumatoid synovium (Komiya et al., 2005).
Distinguishing featuresPhorbol esters and ionomycin upregulate shedding by ADAM10 and ADAM17, but shedding by ADAM15 is unaffected (Maretzky et al., 2009).
Other databases WIKIPEDIAhttp://en.wikipedia.org/wiki/ADAM15
Human genetics
Gene symbol Locus Megabases Ensembl Entrez gene Gene Cards OMIM
ADAM15 1q21.3 ENSG00000143537 8751 ADAM15 605548
Mouse genetics
Gene symbol Position Megabases Ensembl Entrez gene MGI
Adam15 3:F1 ENSMUSG00000028041 11490 MGI:1333882