ADAMTS7B, the Full-length Product of the ADAMTS7 Gene, Is a Chondroitin Sulfate Proteoglycan Containing a Mucin Domain

We have characterized ADAMTS7B, the authentic full-length protein product of the ADAMTS7 gene. ADAMTS7B has a domain organization similar to that of ADAMTS12, with a total of eight thrombospondin type 1 repeats in its ancillary domain. Of these, seven are arranged in two distinct clusters that are separated by a mucin domain. Unique to the ADAMTS family, ADAMTS7B is modified by attachment of the glycosaminoglycan chondroitin sulfate within the mucin domain, thus rendering it a proteoglycan. Glycosaminoglycan addition has potentially important implications for ADAMTS7B cellular localization and for substrate recognition. Although not an integral membrane protein, ADAMTS7B is retained near the cell surface of HEK293F cells via interactions involving both the ancillary domain and the prodomain. ADAMTS7B undergoes removal of the prodomain by a multistep furin-dependent mechanism. At least part of the final processing event, i.e. cleavage following Arg220 (mouse sequence annotation), occurs at the cell surface. ADAMTS7B is an active metalloproteinase as shown by its ability to cleave α2-macroglobulin, but it does not cleave specific peptide bonds in versican and aggrecan attacked by ADAMTS proteases. Together with ADAMTS12, whose primary structure also predicts a mucin domain, ADAMTS7B constitutes a unique subgroup of the ADAMTS family. We have characterized ADAMTS7B, the authentic full-length protein product of the ADAMTS7 gene. ADAMTS7B has a domain organization similar to that of ADAMTS12, with a total of eight thrombospondin type 1 repeats in its ancillary domain. Of these, seven are arranged in two distinct clusters that are separated by a mucin domain. Unique to the ADAMTS family, ADAMTS7B is modified by attachment of the glycosaminoglycan chondroitin sulfate within the mucin domain, thus rendering it a proteoglycan. Glycosaminoglycan addition has potentially important implications for ADAMTS7B cellular localization and for substrate recognition. Although not an integral membrane protein, ADAMTS7B is retained near the cell surface of HEK293F cells via interactions involving both the ancillary domain and the prodomain. ADAMTS7B undergoes removal of the prodomain by a multistep furin-dependent mechanism. At least part of the final processing event, i.e. cleavage following Arg220 (mouse sequence annotation), occurs at the cell surface. ADAMTS7B is an active metalloproteinase as shown by its ability to cleave α2-macroglobulin, but it does not cleave specific peptide bonds in versican and aggrecan attacked by ADAMTS proteases. Together with ADAMTS12, whose primary structure also predicts a mucin domain, ADAMTS7B constitutes a unique subgroup of the ADAMTS family. The extracellular matrix (ECM) 1The abbreviations used are: ECM, extracellular matrix; TSR, thrombospondin type 1 repeat; ORF, open reading frame; PNGase F, peptide N-glycosidase F; CHO, Chinese hamster ovary; GAG, glycosaminoglycan; PBS, phosphate-buffered saline; CS, chondroitin sulfate.1The abbreviations used are: ECM, extracellular matrix; TSR, thrombospondin type 1 repeat; ORF, open reading frame; PNGase F, peptide N-glycosidase F; CHO, Chinese hamster ovary; GAG, glycosaminoglycan; PBS, phosphate-buffered saline; CS, chondroitin sulfate. is an information-rich assembly influencing cell proliferation, apoptosis, and cell migration. Proteases have an essential role in modulating the environmental cues that ECM provides for tissue morphogenesis, homeostasis, and disease progression. Metalloproteases, especially matrix metalloproteases, have a conspicuous role in ECM degradation as well as in proteolysis of cell-surface and soluble proteins (1Somerville R.P. Oblander S.A. Apte S.S. Genome Biology. 2003; (http://genomebiology.com/2003/4/1/reviews/216)PubMed Google Scholar, 2Sternlicht M.D. Werb Z. Annu. Rev. Cell Dev. Biol. 2001; 17: 463-516Crossref PubMed Scopus (3172) Google Scholar). Another metalloprotease family, ADAM (adisintegrin and metalloprotease domain), contains transmembrane enzymes with a major role in ectodomain shedding of cell-surface molecules, but a negligible function in ECM proteolysis (3Blobel C.P. Cell. 1997; 90: 589-592Abstract Full Text Full Text PDF PubMed Scopus (329) Google Scholar). The active site of ADAM proteases, unlike that of the matrix metalloproteases, is of the reprolysin (snake venom zinc metalloprotease) type (3Blobel C.P. Cell. 1997; 90: 589-592Abstract Full Text Full Text PDF PubMed Scopus (329) Google Scholar). 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Apte S.S. Biol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, M.D. S.A. C.P. PubMed Scopus Google Scholar). have in the and ECM PubMed Scopus Google Scholar). by its ability to the Biol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). in to the has in to Apte S.S. 2003; PubMed Scopus Google Scholar). Although in has the and of the of the ADAMTS and to as enzymes a ADAMTS7 and ADAMTS7 and ADAMTS7B is the full-length protein product of in both is a of protein that Apte S.S. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The is used for ADAMTS and ADAMTS7 and ADAMTS7B is the full-length protein product of in both is a of protein that Apte S.S. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The is used for ADAMTS proteases. as an two and a similar domain structure to and Apte S.S. Biol. 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