ADAM metalloproteases
The ADAM metalloproteases , ( English A D isintegrin A nd M etalloproteinase = "a disintegrin and metalloproteinase "), are a group of enzymes that belong to the Metzinkinen - a subclass of the metalloproteinases. As a cofactor one is zinc - Ion needed. To date, over 30 orthologous ADAMs are known. There are also splice variants .
construction
ADAM metalloproteases are integral transmembrane proteins of type I ( single pass ). They usually consist of 800 to 1200 amino acids . The C-terminus is in the intracellular space . This is followed by the transmembrane area, which in the extracellular space of some ADAMs is followed by an EGF- like domain. The subsequent cysteine-rich domain is followed by the disintegrin domain. Then comes the metalloprotease domain. A pro-domain with an N-terminus terminates the ADAM protein. The prodomain has to be split off for the enzyme to be activated. The pro-domain deactivates the metalloprotease domain by means of a cysteine switch . Conserved cysteine residues in the prodomain also coordinate the zinc ion (Zn 2+ ) necessary for the function of the enzyme within the metalloprotease domain. This brings the metalloprotease domain into an inactive conformation, which deactivates the entire enzyme. The prodomain can be split off by furin or other proprotein convertases , so that the zinc ion is only coordinated by the metalloprotease domain and the enzyme is activated.
Stronger complexing agents, such as EDTA , bind the zinc and deactivate the ADAM protease (reversibly).
The disintegrin domain bears its name because of the high structural analogy to the disintegrins in snake venom ( snake venom metalloprotease , SVMP).
function
The ADAM metalloproteases are directly involved in a number of cell biological processes. For example, they play an important role in membrane fusion , muscle development , cell differentiation , cell migration and inflammatory reactions . The ADAMs are also involved in cutting other transmembrane proteins, known as ectodomain shedding . For example, the amyloid precursor protein (APP) is "correctly" cut by the ADAM metalloproteases ADAM9, ADAM10 and ADAM17 - which belong to the α-secretases .
Of the known human ADAM proteases, twelve are predicted to have proteolytic activity. So far, the proteolytic activity has only been measured in half of them. The selectivity or specificity of the ADAM proteases has not yet been established. Some ADAMs belong to the Sheddases .
Occurrence
The ADAM metalloproteases are found in all vertebrates . Cells of the model organisms Caenorhabditis elegans , Drosophila and Xenopus also express ADAMs. In contrast, they are not found on the cell membranes of Escherichia coli and Saccharomyces cerevisiae . They are also absent from plants . The individual ADAMs are expressed to different degrees depending on the cell type.
Individual evidence
- ↑ Family M12 at MEROPS
- ↑ EC 3.4.24.-
- ↑ a b c F. Scholz: Influence of the disintegrin-like metalloproteinase ADAM10 on the proteolytic cleavage of transmembrane proteins of the skin. Dissertation, Christian-Albrechts-Universität zu Kiel, 2006. urn : nbn: de: gbv: 8-diss-18259
- ^ HE Van Wart and H. Birkedal-Hansen: The cysteine switch: A principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. In: PNAS 87, 1990, pp. 5578-5582. PMID 2164689
- ↑ a b c d D. F. Seals and SA Courtneidge: The ADAMs family of metalloproteases: multidomain proteins with multiple functions. In: Genes Dev 17, 2003, pp. 7-30. PMID 12514095 (Review)
- ↑ CP Blobel: Functional and biochemical characterization of ADAMs and their predicted role in protein ectodomain shedding. In: Inflamm Res 51, 2002, pp. 83-84. PMID 11926318 (Review)
- ↑ SF Lichtenthaler: Ectodomain shedding of the amyloid precursor protein: cellular control mechanisms and novel modifiers. In: Neurodegener Dis 3, 2006, pp. 262-269. PMID 17047366 (Review)
- ↑ Gregor Larbig: Studies to identify & optimize potential active ingredients for the treatment of Alzheimer's disease. Dissertation, TU Darmstadt, 2007
literature
Review article
- P. Primakoff and DG Myles: The ADAM gene family: surface proteins with adhesion and protease activity. In: Trends Genet 16, 2000, pp. 83-87. PMID 10652535
- S. Higashiyama and D. Nanba: ADAM-mediated ectodomain shedding of HB-EGF in receptor cross-talk. In: Biochim Biophys Acta 1751, 2005, pp. 110-117. PMID 16054021
- CP Blobel: ADAMs: key components in EGFR signaling and development. In: Nat Rev Mol Cell Biol 6, 2005, pp. 32-43. PMID 15688065
- LC Bridges and RD Bowditch: ADAM-Integrin Interactions: potential integrin regulated ectodomain shedding activity. In: Curr Pharm Des 11, 2005, pp. 837-847. PMID 15777238
- J. Schlöndorff and CP Blobel: Metalloprotease-disintegrins: modular proteins capable of promoting cell-cell interactions and triggering signals by protein-ectodomain shedding. In: J Cell Sci 112, 1999, pp. 3603-3617. PMID 10523497
- DR Edwards et al: The ADAM metalloproteinases. In: Mol Aspects Med 29, 2008, pp. 258-289. PMID 18762209
- TG Wolfsberg et al .: ADAM, a novel family of membrane proteins containing A Disintegrin And Metalloprotease domain: multipotential functions in cell-cell and cell-matrix interactions. In: J Cell Biol 131, 1995, pp. 275-278. PMID 7593158
Reference books
- NM Hooper and U. Lendeckel: The Adam Family of Proteases. Verlag Birkhäuser, 2005, ISBN 0-387-25149-9