Cloning and characterization of ADAMTS-14, a novel ADAMTS displaying high homology with ADAMTS-2 and ADAMTS-3.
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 non-fully 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 ADAMTS-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.
Colige
Alain
A
Laboratory of Connective Tissues Biology, Experimental Cancerology Research Center, Tour de Pathologie (B23/3), University of Liège, B-4000 Liège, Belgium.
Vandenberghe
Isabel
I
Thiry
Marc
M
Lambert
Charles A
CA
Van Beeumen
Jozef
J
Li
Shi-Wu
SW
Prockop
Darwin J
DJ
Lapiere
Charles M
CM
Nusgens
Betty V
BV
D020121:5' Untranslated Regions / Q000235:genetics; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; D000071121:ADAMTS4 Protein; D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D003094:Collagen / Q000648:ultrastructure; D024043:Collagen Type II / Q000235:genetics; D017931:DNA Primers; D018076:DNA, Complementary; D004535:Ehlers-Danlos Syndrome / Q000235:genetics; D006801:Humans; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010446:Peptide Fragments; D016133:Polymerase Chain Reaction; D011348:Procollagen N-Endopeptidase / Q000172:deficiency / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012867:Skin / Q000201:enzymology; D013379:Substrate Specificity; D013710:Tendons / Q000201:enzymology
D020121:5' Untranslated Regions; D024043:Collagen Type II; D017931:DNA Primers; D018076:DNA, Complementary; D010446:Peptide Fragments; D003094:Collagen; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C447060:ADAMTS14 protein, human; D008666:Metalloendopeptidases; C000609307:ADAMTS2 protein, human; C000609308:Adamts2 protein, mouse; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein