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A disintegrin & metalloproteinase domain 10; Kuzbanian protein homolog; mammalian disintegrin-metalloprotease; CDw156; CD156c (ADAM10, KUZ, MADM)

Function: - cleaves the membrane-bound precursor of TNF-alpha at '76-Ala-|-Val-77' to its mature soluble form - responsible for the proteolytic release of several other cell-surface proteins, including: a) heparin-binding epidermal growth-like factor b) ephrin-A2 - responsible for constitutive & regulated alpha-secretase cleavage of amyloid precursor protein (APP) - contributes to the normal cleavage of the cellular prion protein - involved in the cleavage of the adhesion molecule L1 at the cell surface & in released membrane vesicles, suggesting a vesicle-based protease activity - controls also the proteolytic processing of Notch & mediates lateral inhibition during neurogenesis (putative) - interacts with ephrin-A2 (putative) - precursor is cleaved by a furin endopeptidase - EPH receptor binding triggers cleavage - inhibited by TIMP1 & TIMP3, but not TIMP2 & TIMP4 - activity may be enhanced by cholesterol or cholesterol esters [3] - transcription enhanced by SIRT1 deacetylation of RARB - activity induces notch pathway involved in repair of damaged neurons [5] Cofactor: binds 1 Zn+2 (putative) Structure: - conserved Cys present in the cysteine-switch motif binds the catalytic Zn+2, thus inhibiting the enzyme; dissociation of the Cys from the Zn+2 upon the activation-peptide release activates the enzyme - contains 1 disintegrin domain - contains 1 peptidase M12B domain Compartment: - plasma membrane - intracytoplasmic membrane - predominantly localized in the Golgi & in released membrane vesicles derived from the Golgi Expression: - expressed in spleen, lymph node, thymus, peripheral blood leukocyte, bone marrow, cartilage, chondrocytes & fetal liver Pathology: - expressed in osteoarthritis affected-cartilage - low levels of ADAM10 in psoriasis may be attributable to its regulatory role in keratinocyte differentiation and proliferation [6]

General

ADAM (A disintegrin & metalloproteinase domain); MDC (metalloproteinase, disintegrin, cysteine-rich) protein APP alpha-secretase cluster-of-differentiation antigen; cluster designation antigen; CD antigen

Properties

SIZE: entity length = 748 aa MW = 84 kD COMPARTMENT: cytoplasm golgi MOTIF: signal sequence {1-19} Cysteine switch {171-178} MOTIF: Zn+2-binding site SITE: 173-173 Peptidase M12B {220-456} MOTIF: cysteine residue {C222} MODIFICATION: cysteine residue {C313} N-glycosylation site {N267} N-glycosylation site {N278} cysteine residue {C313} MODIFICATION: cysteine residue {C222} cysteine residue {C344} MODIFICATION: cysteine residue {C451} Zn+2-binding site SITE: 383-383 glutamate residue {E384} Zn+2-binding site SITE: 387-387 Zn+2-binding site SITE: 393-393 cysteine residue {C399} MODIFICATION: cysteine residue {C435} cysteine residue {C435} MODIFICATION: cysteine residue {C399} N-glycosylation site {N439} cysteine residue {C451} MODIFICATION: cysteine residue {C344} disintegrin domain {457-551} MOTIF: cysteine residue {C503} MODIFICATION: cysteine residue {C511} cysteine residue {C511} MODIFICATION: cysteine residue {C503} cysteine residue {C524} MODIFICATION: cysteine residue {C543} cysteine residue {C530} MODIFICATION: cysteine residue {C562} cysteine residue {C543} MODIFICATION: cysteine residue {C524} N-glycosylation site {N551} cysteine-rich region {555-673} MOTIF: cysteine residue {C555} MODIFICATION: cysteine residue {C567} cysteine residue {C562} MODIFICATION: cysteine residue {C530} cysteine residue {C567} MODIFICATION: cysteine residue {C555} cysteine residue {C572} MODIFICATION: cysteine residue {C598} cysteine residue {C580} MODIFICATION: cysteine residue {C607} cysteine residue {C582} MODIFICATION: cysteine residue {C597} cysteine residue {C597} MODIFICATION: cysteine residue {C582} cysteine residue {C598} MODIFICATION: cysteine residue {C572} cysteine residue {C607} MODIFICATION: cysteine residue {C580} transmembrane domain {673-693} SH3-binding site NAME: SH3-binding site SITE: 708-715 SH3-binding site NAME: SH3-binding site SITE: 722-728

Database Correlations

OMIM 602192 UniProt O14672 PFAM correlations Entrez Gene 102 Kegg hsa:102 ENZYME 3.4.24.81

References

  1. OMIM :accession 602192
  2. Yong VW et al Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci. 2001 Jul;2(7):502-11. Review. PMID: 11433375
  3. Marx J. Science 294:508, 2001
  4. UniProt :accession O14672
  5. Donmez G et al. SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10. Cell 2010 Jul 23; 142:320 PMID: 20655472 - Wolfe MS and Selkoe DJ. Giving Alzheimer's the old one-two. Cell 2010 Jul 23; 142:194 PMID: 20655461
  6. Gul C, Kilic S, Sehitoglu MH. The importance of ADAM10 and ADAM17 metalloproteinases in the pathogenesis of psoriasis. Clin Exp Dermatol. 2022. April 26 PMID: 35474465