ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif) is a novel family of extracellular proteinases. Presently eighteen family members have been identified in the human genome. ADAMTS4 was first purified from Il-1-stimulated bovine nasal cartilage conditioned media and human ADAMTS4-cDNA was cloned from a human heart cDNA library. ADAMTS4 consists of a prodomain, a catalytic domain, a disintegrin domain, a thrombospondin type-1 motif and a Cys-rich region followed by a C-terminal sequence. The prodomain is most likely cleaved off by a furin-type enzyme before ADAMTS4 is released from cells. ADAMTS4 hydrolyzes aggrecan, the major proteoglycan of articular cartilage. As aggrecan is also digested by 2 other members of the ADAMTS family, ADAMTS1 and ADAMTS5, aggrecan degradation products found in normal and rheumatoid and osteoarthritic joint cartilage may arise from action of either of the 3 proteinases. Isolated ADAMTS4 hydrolyzes aggrecan at 5 different sites. Four cleavage sites are located in the chondroitin sulfate-rich region between globular domains G2 and G3, while one site is placed in the rod-shaped polypeptide between globular domains G1 and G2. The thrombospondin motif in ADAMTS4 appears to be critical for aggrecan substrate recognition and cleavage. ADAMTS4 hydrolyzes also other lecticans as brevican and versican. ADAMTS4 is inhibited by TIMP 3 [10] and by the N-terminal domain of TIMP 3 with Ki-values in the nanomolar range. Inhibition by TIMP 1, 2, and 4 is much weaker.
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