Cloning and Characterization of ADAMTS-14, a Novel ADAMTS Displaying High Homology with ADAMTS-2 and ADAMTS-3

Abstract

The processing of amino-and carboxyl-propeptides of fibrillar collagens is required to generate collagen monomers that correctly assemble into fibrils. Mutations in the ADAMTS2 gene, the aminopropeptidase of procollagen I and II, result in the accumulation of nonfully processed type I procollagen, causing human Ehlers-Danlos syndrome type VIIC and animal dermatosparaxis. In this study, we show that the aminopropeptide of type I procollagen can be cleaved in vivo in absence of ADAMTS-2 activity and that this processing is performed at the cleavage site for ADAMTS-2. In an attempt to identify the enzyme responsible for this alternative aminoprocollagen peptidase activity, we have cloned the cDNA and determined the primary structure of human and mouse ADAMTS-14, a novel ADAMTS displaying striking homologies with ADAMTS-2 and -3. The structure of the human gene, which maps to 10q21.3, and the mechanisms of generation of the various transcripts are described. The existence of two sites of initiation of transcription, in two different promoter contexts, suggests that transcripts resulting from these two sites can be differently regulated. The tissue distribution of AD-AMTS-14, the regulation of the gene expression by various cytokines and the activity of the recombinant enzyme are evaluated. The potential function of ADAMTS-14 as a physiological aminoprocollagen peptidase in vivo is discussed. ADAMTS1 (A Disintegrin and metalloprotease with thrombospondin type I repeats) is a novel family of metalloproteases found in vertebrates and invertebrates. These enzymes are related to ADAMs as judged from sequence homology and conserved domains such as a characteristic metalloprotease domain and a disintegrin-like module. However, they differ from ADAMs by their domain organization and the presence of distinct features. The most specific hallmark is the presence of a central thrombospondin type I repeat (TSPI) between the disintegrin-like module and the Cys-rich domain. All ADAMTS, except ADAMTS-4, contain also TSPI-like domains in varying numbers at the COOH terminus (1, 2). Currently, 12 ADAMTS from vertebrates and a few from invertebrates (Drosophila and Caenorhabditis elegans) have been described (1, 2). AD-AMTS-1, -4, and -5 are able to cleave proteoglycans and are probably involved in cartilage degradation during arthritis (3-5). ADAMTS-1 and -8 are potent anti-angiogenic molecules (6). Adamts1Ϫ/Ϫ mice display abnormal growth, defective fertility, and altered organ morphology and function (7). A C. elegans Adamts, gon-1, was found essential for gonadal morphogenesis (8). Both the metalloprotease domain and some TSPI-like repeats are required for the control of this process.The primarily described activity of ADAMTS-2 is to excise the aminopropeptide of type I and type II procollagens, explaining its former trivial name aminoprocollagen I/II peptidase (9, 10). Removal of the N-and C-propeptide of type I procollagen is required to generate collagen monomers able to assemble into elongated and cylindrical collagen fibers. H...

ADAMTS14 gene polymorphism associated with knee osteoarthritis in Thai women

“…There are 19 published vertebrate family members of ADAMTSs, numbered 1-10 and 12-20 to date (Cal et al, 2002;Somerville et al, 2003). Although little is still known about its function, ADAMTS14 has high similarities in sequence and domain structure to ADAMTS-2 (56 %) and ADAMTS-3 (63 %) (Colige et al, 2002), which play a major role in the biosynthesis of collagen precursors. There is evidence that these three enzymes have the ability to cleave the N-propeptides of procollagen type I (pNPI activity) and the homotrimeric procollagen type II before they are incorporated into collagen fibers (Lapiere et al, 1971;Tuderman et al, 1978;Hojima et al, 1989Hojima et al, , 1994 .…”

“…There is evidence that these three enzymes have the ability to cleave the N-propeptides of procollagen type I (pNPI activity) and the homotrimeric procollagen type II before they are incorporated into collagen fibers (Lapiere et al, 1971;Tuderman et al, 1978;Hojima et al, 1989Hojima et al, , 1994 . Moreover, ADAMTS14 has been shown to have pNPI activity in vitro, and has been suggested as a possible source of residual pNPI activity observable in the bone, tendon, cartilage, skin, and other tissues of Ehlers-Danlos syndrome type VIIC patients, dermatosparaxic cattle, and Adamts2-null mice (Fernandes et al, 2001;Colige et al, 2002;Le Goff et al, 2006).…”

The Basic Science of Tendinopathy

“…Nineteen ADAMTSs have been identified so far, but many of them remain to be fully characterized [50]. ADAMTS-2, -3, and -14 function as key regulators of collagen fibril assembly [27]. ADAMTS-1 and -4 are capable of cleaving certain matrix proteoglycans such as versican, brevican, and aggrecan [81,113].…”

Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity

“…Additional approaches attempting to determine the genetic cause of congenital TTP also discovered the same gene, ADAMTS13 (22). VWF-CP͞ADAMTS-13 is a member of the ADAMTS family of metalloproteases, named for the characteristic combination of a disintegrin-like and metalloprotease with thrombospondin type 1 (TSP1) motif (23)(24)(25)(26). VWF-CP is predominantly expressed in liver (18,21,22,25), consistent with our previous observation that severely decreased levels of plasma VWF-CP activity in patients with biliary atresia can be restored by living-related liver transplantation.…”