ADAMs a disintegrin and

ADAM a disintegrin and metaUoprotease ASTIN acute stroke therapy by inhibition of... 

ADAM. A Disintesrin And MetalloProteinase family of proteins. Disintegrins, as the name implies, are proteins which interfere with interactions of cells with proteins in the extracellular matrix. An example are the inhibitors of the interaction of blood platelets with fibrinogen. Disintegrins are found in snake venom. Metalloproteinases are a family of proteases which need a bivalent cation for catalysis. MMP s are matrix metallo-proteases. They are associated with the extracellular matrix. 

ADAMs are membrane proteins that contain a disintegrin and a metalloprotease domain. Disintegrins are RGD-containing proteins that inhibit cell/matrix interactions (adhesion) and cell/cell interactions (aggregation) through the integrin receptors. In addition, ADAMs have two other domains that are involved in signaling and transport (113). 

Wolfsberg, T.G., Primakoff, P., Myles, D.G., and White, J.M. (1995). ADAM, a novel family of membrane proteins containing a disintegrin and metalloprotease domain Multipotential functions in cell-cell and cell-matrix interactions. J. Cell Biol. 797 1-4. 

APP = Amyloid Precursor Protein, P97 = mellanotransferrin, PS-1 == Presenillin-1 and PS-2 = Presenillin-2, ADAM-10 = A Disintegrin and Metalloprotease Domain-10, and ADAM-17 = = A Disintegrin and Metalloprotease Domain 17, TACE-1 = Tumor Necrosis Factor alpha Converting Enzyme, ORF = Open Reading Frame. 

Fig. 1.2 A scheme of the activation of ADAMs and of the shedding process. The dimeric ADAM proteases and their substrates are anchored in the membrane, but are separated from each other. Upon activation (via protein kinases ), the protease is disengaged from disintegrin and associates with the substrate. Proteolysis takes place and the free, soluble ectodomains of membrane-anchored cell-surface proteins are shed from the membrane-anchored substrates and released. (Reproduced from ref. 3, with permission of the authors and Science.)...

TNF-a converting enzyme (TACE) is a newly discovered enzyme in the disintegrin and metalloproteinase (ADAM) family (78). This enzyme releases the 17-kD mature TNF-a fiom membrane-bound TNF-a by cleaving Ala 76 and Val 77 linkage. TACE has also been shown to be involved with other cell surface protein shedding events such as the p55 and p75 TNF-a receptors (79). Our laboratory has previously shown that acute administration of alcohol (EtOH)to rats suppresses TNF-a production posttranscriptionally in the lung and blood (20,80). Recently, we have further defined the mechanism of TNF-a inhibition by EtOH, which revealed... 

Ludwig A, Hundhausen C, Lambert MH, et al. Metalloproteinase inhibitors for the disintegrin-like metalloproteinases ADAM 10 and ADAM 17 that differentially block constitutive and phorbol ester-inducible shedding of cell surface molecules. Comb Chem High Throughput Screen 2005 8 161-171. 

Yuan, R., Primakoff, P., and Myles, D.G. (1997). A role for the disintegrin domain of cyritestin, a sperm surface protein belonging to the ADAM family, in mouse sperm-egg plasma membrane adhesion and fusion. J. Cell Biol. 797 105-112. 

Abel, S., Hundhausen, C., Mentlein, R., Schulte, A., Berkhout, T. A., Broadway, N., Hartmann, D., Sedlacek, R., Dietrich, S., Muetze, B., Schuster, B., Kallen, K. J., Saftig, P., Rose-John, S., and Ludwig, A. (2004). The transmembrane CXC-chemokine ligand 16 is induced by IFN-gamma and TNF-alpha and shed by the activity of the disintegrin-like metalloproteinase ADAM 10. J. Immunol. 172, 6362-6372. 

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