We report the primary structure of three novel, putative zinc metalloproteases designated ADAM-TS5, ADAM-TS6, and ADAM-TS7. All have a similar domain organization, comprising a preproregion, a reprolysintype catalytic domain, a disintegrin-like domain, a thrombospondin type-1 (TS) module, a cysteine-rich domain, a spacer domain without cysteine residues, and a COOH-terminal TS module. These genes are differentially regulated during mouse embryogenesis and in adult tissues, with Adamts5 highly expressed in the periimplantation period in embryo and trophoblast. These proteins are similar to four other cognate gene products, defining a distinct family of human reprolysin-like metalloproteases, the ADAM-TS family. The other members of the family are ADAM-TS1, an inflammation-induced gene, the procollagen I/II amino-propeptide processing enzyme (PCINP, ADAM-TS2), and proteins predicted by the KIAA0366 and KIAA0688 genes (ADAM-TS3 and ADAM-TS4). Individual ADAM-TS members differ in the number of COOH-terminal TS modules, and some have unique COOH-terminal domains. The ADAM-TS genes are dispersed in human and mouse genomes.
Proteolysis of extracellular matrix (ECM)1 plays a critical role in establishing tissue architecture during development and in tissue degradation in diseases such as cancer, arthritis, Alzheimer's disease, and a variety of inflammatory conditions (1-3). The proteolytic enzymes responsible include members of diverse protease families and they may work in concert or in cascades to degrade or process molecules. Two groups of zinc metalloproteases in particular, ADAMs (a disintegrin and metalloprotease) (2-4) and MMPs (matrix metalloproteinases) (1), appear broadly relevant to extracellular proteolysis. These families include a large number of enzymes (over 20 gene products each) with demonstrated cleavage activity for matrix molecules as well as nonmatrix, bioactive molecules such as tumor necrosis factor-␣ (reviewed in Ref. 3). In other instances of extracellular proteolysis, such as cleavage of aggrecan at the Glu 373 -Ala 374 peptide bond (5) or the shedding of L-selectin from leukocytes (6), the responsible proteases have not yet been reported. Such activities may eventually be attributed to cognate proteases but they may well be due to one or more hitherto unknown enzymes. For these reasons, it is important to define the full repertoire of enzymes possessed by cells, their regulation, and their substrate preferences.ADAMs, also referred to as MDC (metalloprotease-disintegrins with cysteine-rich domains, 2) have catalytic domains with zinc-binding signatures and disintegrin domains that are very similar to the snake venom metalloproteinases (reviewed in Ref. 7); together, the ADAMs and snake venom metalloproteinases are referred to as reprolysins (7). Most ADAM members are quite similar in domain organization (2, 4, 7), bearing from amino to carboxyl termini, a signal peptide, a proregion, a zinc-metalloprotease catalytic domain with the typical reprolysin signature HEX 1 X 2 HX 3 X 1 GX 1 XHD (X i...
