Identification of Prodomain Determinants Involved in ADAMTS-1 Biosynthesis

The metalloprotease ADAMTS-1 (adisintegrin and metalloprotease with thrombospondin type I motif), similarly to other members of the ADAMTS family, is initially synthesized as a zymogen, proADAMTS-1, that undergoes proteolytic processing at the prodomain/catalytic domain junction by serine proteinases of the furin-like family of proprotein convertases. The goals of this study were to identify residues of the prodomain that play an essential role in ADAMTS-1 processing and to determine the identity of the convertase required for zymogen processing. To gain insight into the putative roles of specific prodomain residues in ADAMTS-1 biosynthesis, we performed biosynthetic labeling experiments in transiently transfected human embryonic kidney 293 cells expressing wild-type and prodomain mutants of proADAMTS-1. Cells expressing wild-type ADAMTS-1 initially produced a 110-kDa zymogen form that was later converted to an 87-kDa form, which was also detected in the media. Although convertases such as PACE4 and PC6B processed proADAMTS-1, we found that furin was the most efficient enzyme at producing the mature ADAMTS-1 87-kDa moiety. Site-directed mutagenesis of the two putative furin recognition sequences found within the ADAMTS-1 prodomain (RRNR173 and RKKR235) revealed that Arg235 was the sole processing site. Use of the Golgi disturbing agent, Brefeldin A, and monensin suggests that the cleavage of proADAMTS-1 takes place in the Golgi apparatus prior to its secretion. Conserved residues within the prodomain of other ADAMTS members hinted that they might act as maturation determinants. Replacement with alanine of selected residues Cys106, Tyr108, Gly110, Cys125, and Cys181 and residues encompassing the 137-144 sequence significantly affected the biosynthetic profile of the enzyme. Our results suggest that conserved residues other than the furin cleavage site in the prodomain of ADAMTS-1 are involved in its biosynthesis. The metalloprotease ADAMTS-1 (adisintegrin and metalloprotease with thrombospondin type I motif), similarly to other members of the ADAMTS family, is initially synthesized as a zymogen, proADAMTS-1, that undergoes proteolytic processing at the prodomain/catalytic domain junction by serine proteinases of the furin-like family of proprotein convertases. The goals of this study were to identify residues of the prodomain that play an essential role in ADAMTS-1 processing and to determine the identity of the convertase required for zymogen processing. To gain insight into the putative roles of specific prodomain residues in ADAMTS-1 biosynthesis, we performed biosynthetic labeling experiments in transiently transfected human embryonic kidney 293 cells expressing wild-type and prodomain mutants of proADAMTS-1. Cells expressing wild-type ADAMTS-1 initially produced a 110-kDa zymogen form that was later converted to an 87-kDa form, which was also detected in the media. Although convertases such as PACE4 and PC6B processed proADAMTS-1, we found that furin was the most efficient enzyme at producing the mature ADAMTS-1 87-kDa moiety. Site-directed mutagenesis of the two putative furin recognition sequences found within the ADAMTS-1 prodomain (RRNR173 and RKKR235) revealed that Arg235 was the sole processing site. Use of the Golgi disturbing agent, Brefeldin A, and monensin suggests that the cleavage of proADAMTS-1 takes place in the Golgi apparatus prior to its secretion. Conserved residues within the prodomain of other ADAMTS members hinted that they might act as maturation determinants. Replacement with alanine of selected residues Cys106, Tyr108, Gly110, Cys125, and Cys181 and residues encompassing the 137-144 sequence significantly affected the biosynthetic profile of the enzyme. Our results suggest that conserved residues other than the furin cleavage site in the prodomain of ADAMTS-1 are involved in its biosynthesis. Proteolysis of extracellular substrates by the ADAMTS 1The abbreviations used are: ADAMTS, adisintegrin and metalloprotease with thrombospondin type I motif; PC, proprotein convertase; MMP, matrix metalloproteinases; CHO RPE.40, Chinese hamster ovary resistance to Pseudomonas exotoxin A. (adisintegrin and metalloprotease with thrombospondin type I motif) family, which consists of at least 19 members, is an important mechanism regulating events such as cartilage biosynthesis, angiogenesis, and cell motility and growth (1Iruela-Arispe M.L. Carpizo D. Luque A. Ann. N. Y. Acad. Sci. 2003; 995: 183-190Crossref PubMed Scopus (86) Google Scholar). The first member, ADAMTS-1 (peptidase M12.222, Merops data base), identified as a cachexia-associated gene expressed in colon tumor cells (2Kuno K. Kanada N. Nakashima E. Fujiki F. Ichimura F. Matsushima K. J. Biol. Chem. 1997; 272: 556-562Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar), along with ADAMTS-4 and ADAMTS-5 (also called aggrecanases), degrades to different extents the cartilage proteoglycan aggrecan and lectican or aggrecan-like proteins such as brevican and versican. This suggested a significant participation of these enzymes in conditions such as arthritis (3Tortorella M.D. Burn T.C. Pratta M.A. Abbaszade I. Hollis J.M. Liu R. Rosenfeld S.A. Copeland R.A. Decicco C.P. Wynn R. Rockwell A. Yang F. Duke J.L. Solomon K. George H. Bruckner R. Nagase H. Itoh Y. Ellis D.M. Ross H. Wiswall B.H. Murphy K. Hillman Jr., M.C. Hollis G.F. Newton R.C. Magolda R.L. Trzaskos J.M. Arner E.C. Science. 1999; 284: 1664-1666Crossref PubMed Scopus (620) Google Scholar, 4Abbaszade I. Liu R.Q. Yang F. Rosenfeld S.A. Ross O.H. Link J.R. Ellis D.M. Tortorella M.D. Pratta M.A. Hollis J.M. Wynn R. Duke J.L. George H.J. Hillman Jr., M.C. Murphy K. Wiswall B.H. Copeland R.A. Decicco C.P. Bruckner R. Nagase H. Itoh Y. Newton R.C. Magolda R.L. Trzaskos J.M. Hollis G.F. Arner E.C. Burn T.C. J. Biol. Chem. 1999; 274: 23443-23450Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar, 5Sandy J.D. Westling J. Kenagy R.D. Iruela-Arispe M.L. Verscharen C. Rodriguez-Mazaneque J.C. Zimmermann D.R. Lemire J.M. Fischer J.W. Wight T.N. Clowes A.W. J. Biol. Chem. 2001; 276: 13372-13378Abstract Full Text Full Text PDF PubMed Scopus (376) Google Scholar, 6Matthews R.T. Gary S.C. Zerillo C. Pratta M. Solomon K. Arner E.C. Hockfield S. J. Biol. Chem. 2000; 275: 22695-22703Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar). ADAMTS-1 is also anti-angiogenic, a property possibly explained by the recent finding that it sequesters vascular endothelial growth factor-1 (7Luque A. Carpizo D.R. Iruela-Arispe M.L. J. Biol. Chem. 2003; 278: 23656-23665Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar). The phenotype of ADAMTS-1-/- mice revealed marked reduction in size with body weights of ∼70% of their wild-type or heterozygous littermates, and fertilization was impaired in females (8Shindo T. Kurihara H. Kuno K. Yokoyama H. Wada T. Kurihara Y. Imai T. Wang Y. Ogata M. Nishimatsu H. Moriyama N. Oh-hashi Y. Morita H. Ishikawa T. Nagai R. Yazaki Y. Matsushima K. J. Clin. Investig. 2000; 105: 1345-1352Crossref PubMed Scopus (272) Google Scholar). ADAMTS-2, ADAMTS-14, and ADAMTS-3 are procollagen N-proteinases that proteolytically remove amino peptides in the processing of type I and type II procollagens to collagens (9Colige A. Sieron A.L. Li S.W. Schwarze U. Petty E. Wertelecki W. Wilcox W. Krakow D. Cohn D.H. Reardon W. Byers P.H. Lapiere C.M. Prockop D.J. Nusgens B.V. Am. J. Hum. Genet. 1999; 65: 308-317Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar, 10Colige A. Vandenberghe I. Thiry M. Lambert C.A. Van Beeumen J. Li S.W. Prockop D.J. Lapiere C.M. Nusgens B.V. J. Biol. Chem. 2002; 277: 5756-5766Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, 11Fernandes R.J. Hirohata S. Engle J.M. Colige A. Cohn D.H. Eyre D.R. Apte S.S. J. Biol. Chem. 2001; 276: 31502-31509Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar). Deficiency of ADAMTS-2 led to an inherited connective tissue disorder called dermatosparaxis in animals and the Ehlers-Danlos syndrome (dermatosparactic-type) in humans. Reports have recently demonstrated that mutations in the ADAMTS-13 gene cause thrombotic thrombocytopenic purpura, a coagulation disorder, and that ADAMTS-13 is required for the processing of large von Willebrand factor multimers (12Levy G.G. Nichols W.C. Lian E.C. Foroud T. McClintick J.N. McGee B.M. Yang A.Y. Siemieniak D.R. Stark K.R. Gruppo R. Sarode R. Shurin S.B. Chandrasekaran V. Stabler S.P. Sabio H. Bouhassira E.E. Upshaw Jr., J.D. Ginsburg D. Tsai H.M. Nature. 2001; 413: 488-494Crossref PubMed Scopus (1449) Google Scholar). The functions of most of the other ADAMTS members remain to be better clarified. The structure of all of the ADAMTS members includes a signal peptide for access to the secretory pathway, a prodomain, a catalytic metalloprotease domain, a disintegrin-like domain, and a carboxyl-terminal ancillary domain having a conserved modular structure but containing a variable number of thrombospondin, type I repeat-like domains (2Kuno K. Kanada N. Nakashima E. Fujiki F. Ichimura F. Matsushima K. J. Biol. Chem. 1997; 272: 556-562Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar). Unlike the ADAM family, the ADAMTS members do not contain a transmembrane domain yet they may be located in the vicinity of the cell via binding to cell surface molecules or the pericellular matrix (13Somerville R.P. Longpre J.M. Jungers K.A. Engle J.M. Ross M. Evanko S. Wight T.N. Leduc R. Apte S.S. J. Biol. Chem. 2003; 278: 9503-9513Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar). Thus ADAMTSs are secreted proteins anchored to the cell surface or to the extracellular matrix (14Kuno K. Terashima Y. Matsushima K. J. Biol. Chem. 1999; 274: 18821-18826Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). ADAMTS proteases, similar to ADAM and MMPs, are synthesized as zymogens, which require activation via the proteolytic removal of a prodomain. The size of the prodomain varies, because it is in part determined by the location of the carboxylterminal most furin-processing site; however, in all of the ADAMTSs with the exception of ADAMTS-13, which has an overall atypical primary structure, the size is ∼200 residues. At least one sequence, but usually multiple furin recognition sequences, occurs in the prodomain of most members of the ADAMTS family. ADAMs, MMPs, and ADAMTS-1, ADAMTS-2, ADAMTS-4, ADAMTS-5, ADAMTS-9, and ADAMTS-12 (3Tortorella M.D. Burn T.C. Pratta M.A. Abbaszade I. Hollis J.M. Liu R. Rosenfeld S.A. Copeland R.A. Decicco C.P. Wynn R. Rockwell A. Yang F. Duke J.L. Solomon K. George H. Bruckner R. Nagase H. Itoh Y. Ellis D.M. Ross H. Wiswall B.H. Murphy K. Hillman Jr., M.C. Hollis G.F. Newton R.C. Magolda R.L. Trzaskos J.M. Arner E.C. Science. 1999; 284: 1664-1666Crossref PubMed Scopus (620) Google Scholar, 4Abbaszade I. Liu R.Q. Yang F. Rosenfeld S.A. Ross O.H. Link J.R. Ellis D.M. Tortorella M.D. Pratta M.A. Hollis J.M. Wynn R. Duke J.L. George H.J. Hillman Jr., M.C. Murphy K. Wiswall B.H. Copeland R.A. Decicco C.P. Bruckner R. Nagase H. Itoh Y. Newton R.C. Magolda R.L. Trzaskos J.M. Hollis G.F. Arner E.C. Burn T.C. J. Biol. Chem. 1999; 274: 23443-23450Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar, 13Somerville R.P. Longpre J.M. Jungers K.A. Engle J.M. Ross M. Evanko S. Wight T.N. Leduc R. Apte S.S. J. Biol. Chem. 2003; 278: 9503-9513Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar, 15Rodriguez-Manzaneque J.C. Westling J. Thai S.N. Luque A. Knauper V. Murphy G. Sandy J.D. Iruela-Arispe M.L. Biochem. Biophys. Res. Commun. 2002; 293: 501-508Crossref PubMed Scopus (208) Google Scholar, 16Cal S. Arguelles J.M. Fernandez P.L. Lopez-Otin C. J. Biol. Chem. 2001; 276: 17932-17940Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 17Wang S. B.M. M.L. M.C. K. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google have to be processed by furin-like proprotein convertases. The convertase family is of serine F. Leduc R. R. J. 2000; PubMed Scopus Google that sequence containing of residues in the and I. A. Biochem. Biophys. Res. Commun. PubMed Scopus Google Scholar). of the most is in the and this and the cell surface the S.S. C. M.C. G. J. Biol. PubMed Scopus Google Scholar). The and of furin are events G. Biol. 2002; PubMed Scopus Google Scholar). zymogen activation is a we have in this the this Although convertases PACE4 and PC6B may proADAMTS-1, we that furin is the most efficient convertase at the proADAMTS-1 at Arg235 of the furin recognition sequence we also identify different conserved residues within the of ADAMTS family members that be involved in the maturation of proADAMTS-1. be of to the of the ADAMTS and cells the human embryonic cell were in containing and CHO cells were in containing and cells were transfected with of of prior to Site-directed ADAMTS-1 in has J.C. Leduc R. Iruela-Arispe M.L. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). The of ADAMTS-1 prodomain mutants was performed the mutagenesis with the is and 137-144 to The different convertases were expressed the The human furin in was J. Longpre J. G. Leduc R. 2002; PubMed Scopus Google Scholar). The PC6B was in of K. The human R. and PACE4 R. E. The of were in of the were by of ADAMTS-1 and human ADAMTS-1 were with a peptide to The peptide residues of the human ADAMTS-1 catalytic The were with a peptide to The peptide residues of the human catalytic were with in an of and experiments were performed Cells were with and in with and of for the of was in the the cell was with and the cells were with of and containing and were to remove ADAMTS-1 C. R. Leduc R. 2000; PubMed Scopus Google Scholar), or was and were at were and for at were with of and proteins were by were with and for Brefeldin at or monensin at or was to the labeling CHO cells were in of of were to and to a was performed with The were with the the to the of proteins cell and of ADAMTS-1 transfected cells was performed of for at in and by and of J.C. Leduc R. Iruela-Arispe M.L. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google processing of proADAMTS-1 is required for its To better the of ADAMTS-1 is involved in the of the we transfected human kidney 293 cells with an containing the human ADAMTS-1 experiments were initially to the of ADAMTS-1 ADAMTS-1 proteins were with a the sequence in the domain of in we detected in cell a a 110-kDa form that to the of proADAMTS-1 a a 87-kDa form to the proteolytically ADAMTS-1 in the cells with a processing of proADAMTS-1 of The mature 87-kDa ADAMTS-1 is also detected in the to a at in the a of processing by a J.C. Leduc R. Iruela-Arispe M.L. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). of labeling and to a at and ADAMTS-1 we the of the with labeling that the of the at an form as be by the significant in to an of in with the of which to mature ADAMTS-1 the two at also to be because are to of by furin is the better proprotein and also proteins within the secretory A. G. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google but their is To these convertases proADAMTS-1, we ADAMTS-1 with the of these different convertases in the CHO cells Genet. PubMed Scopus Google Scholar). be in proADAMTS-1 is processed to in CHO cells by but than in 293 cells as demonstrated by the of the 110-kDa zymogen form in the with the 110-kDa form is detected in the of furin with ADAMTS-1 led to the processing of the 110-kDa form into the 87-kDa and the PACE4 and PC6B also proADAMTS-1 as demonstrated by the of the 110-kDa zymogen form in cells and but not as as processing of proADAMTS-1 was of the different convertases were by convertase with ADAMTS-1 that mature furin of G. Longpre J.M. Leduc R. Biochem. J. PubMed Scopus Google Scholar), PACE4 T. R. K. M. Wada I. A. Y. Biochem. Biophys. Res. Commun. 2002; PubMed Scopus Google Scholar), PC6B of and J.W. J.W. Van J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google are all expressed at similar was by results suggest that proADAMTS-1 is converted to the and by furin to a by and furin in the most expressed of all of the it is to be the zymogen convertase of the ADAMTS family. it is that other of this family may also play a role in zymogen activation Arg235 for ADAMTS family members than one putative furin recognition sequence, within their prodomain. are two putative cleavage (RRNR173 and RKKR235) within the ADAMTS-1 prodomain. To the of one of these ADAMTS-1 biosynthesis, we performed mutagenesis the of cleavage sequence by with and in the of labeling of cells transfected with or by with that the biosynthetic profile of the not that with wild-type cells transfected with the not the 110-kDa form, which is also found in the the of at for other were that the furin recognition site at was not used to other maturation processing was such as the processing of the 87-kDa form into the that these require the cleavage of the zymogen it is that the processed at the of the proteolytically of we processing of proADAMTS-1 in CHO we cleavage in these cells was also the furin recognition that also required Arg235 for because the zymogen form of was in the cell and in the media. these cells with furin not processing into the mature the of Arg235 in the maturation of ADAMTS-1 the proADAMTS-1 activation we cells expressing ADAMTS-1 with the Brefeldin and monensin revealed that Brefeldin A, which the and the Golgi the processing of the 110-kDa proADAMTS-1 form into the and mature The cells were also with a of A. Biol. PubMed Scopus Google Scholar). At monensin with but not the of the mature 87-kDa form that was detected in the this was at these results identify the Golgi as the site of proADAMTS-1 processing. of Conserved ADAMTS-1 determine residues other than the furin recognition sequences are important in the maturation and of ADAMTS-1, we the of ADAMTS family members because conserved residues be required or in these the of the 19 human ADAMTS that of the with the sequence is and amino found in ADAMTS are residues. This conserved residues and in the prodomain of ADAMTS the furin recognition sequences found at the of the Site-directed mutagenesis was performed to the of these conserved amino in the prodomain of the different mutants of ADAMTS-1 used in the was performed in human embryonic cells transfected with different ADAMTS-1 prodomain mutants we found that the zymogen of expressed was detected in cell The and mutants similarly to the wild-type ADAMTS-1 with to their processing residues 137-144 by the processing of the 110-kDa zymogen form into the 87-kDa but this zymogen form to be detected in the media. the and processing was similar to were in the media. significantly of processed of and were found in the media. zymogen of these mutants were detected they were not as secreted as was the furin recognition sequence that zymogen activation is not a for secretion. it be that an overall reduction of be for these that a of these proteins may to that not to act as substrates for processing or for the secretory we the of possibly involved in the an essential in the of other H. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The results that Cys181 with led to the processing of proADAMTS-1 and the of processed in the that this may not be for and activation as demonstrated for most of the Proteolysis of the extracellular matrix and cell surface proteins by MMPs, ADAMs, and is of for and conditions such as tissue and tumor cell and (1Iruela-Arispe M.L. Carpizo D. Luque A. Ann. N. Y. Acad. Sci. 2003; 995: 183-190Crossref PubMed Scopus (86) Google Scholar, C. Biol. 2001; Full Text PDF PubMed Scopus Google Scholar). are synthesized as or most to proteolytic the prodomain located to the catalytic domain be the members of the proprotein convertase family be for the proteolytic cleavage of the prodomain at the junction of the catalytic we that the 110-kDa proADAMTS-1 is processed to a form that secreted as a furin is the most efficient convertase at proADAMTS-1 within the secretory PC6B also the convertases within the G. Biol. 2002; PubMed Scopus Google Scholar), but it has that PACE4 is secreted and to in the extracellular matrix A. K. E. T. S. K. K. Y. Biophys. 2003; PubMed Scopus Google Scholar). it is that PACE4 and PC6B may and proADAMTS-1 in different or conditions of The mechanism for processing proADAMTS-1 in the CHO cells may be by functions of enzymes such as PACE4 or these are as is furin the of a furin-like recognition sequence and Arg235 for cleavage of proADAMTS-1. The that ADAMTS-1 is because is the with most similar to that of furin with which it is A. M. A. J. D. C. S. M. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). or furin-like activation by at the of the conserved found the prodomain and the catalytic and J.C. Westling J. Thai S.N. Luque A. Knauper V. Murphy G. Sandy J.D. Iruela-Arispe M.L. Biochem. Biophys. Res. Commun. 2002; 293: 501-508Crossref PubMed Scopus (208) Google have that a to proADAMTS-1 not Our data that the which also the furin recognition sequence, was not processed by furin and that the zymogen form was This may the of of these it is to in such as and type furin cleavage be used the primary site is T. D. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, I. Biol. 2000; PubMed Scopus Google Scholar). this is not the for ADAMTS-1 because the for in the not to processing at the site. for this is that the site is not in an of the prodomain that is to the and is not to ADAMTS-9, multiple furin-like recognition sequences are found within the prodomain but one is used (13Somerville R.P. Longpre J.M. Jungers K.A. Engle J.M. Ross M. Evanko S. Wight T.N. Leduc R. Apte S.S. J. Biol. Chem. 2003; 278: 9503-9513Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar). Our results also that maturation of proADAMTS-1 is an To the proADAMTS-1 activation we the cells with Brefeldin A, which the the and Golgi apparatus T. K. S. A. Y. J. Biol. Chem. Full Text PDF PubMed Google but of the furin zymogen M. W. S. W. J. Biol. PubMed Scopus Google Scholar). Brefeldin the ADAMTS-1 activation and which suggests that the maturation of proADAMTS-1 by furin the specific of the a of A. Biol. PubMed Scopus Google Scholar), with the of ADAMTS-1 but not its these results that proADAMTS-1 processing takes place in the Golgi of the 19 ADAMTS family members revealed conserved other than the furin recognition sequence at the of the ADAMTS-13, and with other members of the family. one of ADAMTS-13, it has recently demonstrated that removal of its prodomain is not for proteolytic the von Willebrand factor J. Biol. Chem. 2003; Full Text Full Text PDF Scopus Google Scholar). The and conserved ADAMTS-13 to be for and Conserved residues within metalloprotease type have in important for the and of the enzyme M. J. M. W. S. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). a we the of proADAMTS-1 to the of conserved residues biosynthesis. not significant in the biosynthetic of the conserved residues such as in of 19 ADAMTS of 19 but all are in this and of that these amino are not in ADAMTS-1 biosynthesis. of the conserved residues such as in of 19 ADAMTS of of of and residues 137-144 a the of the enzyme with processing and it is important to that it is that of these residues in a of as demonstrated by the overall of detected This that conserved residues in ADAMTS members are important for are as recognition required for their maturation and secretion. The that are by the of a conserved of the prodomain and a in the catalytic domain that the site. of this to the removal of the prodomain and activation of the enzyme H. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). ADAMTS, similar to ADAM and MMP, a conserved and the catalytic in a The within the sequence is the in the mechanism because of the of the amino Cys181 to other found in and I. R. S. J. PubMed Scopus Google Scholar). maturation and activation of the demonstrated that Cys181 is not for the furin Arg235 to maturation the is a for of processing in the mutants also the that this be in or a processing has to have a role and has with ADAMTS proteins ADAMTS-4, and J.C. Leduc R. Iruela-Arispe M.L. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, W. C. T. S.A. T. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). these the of to the ADAMTS important of the ancillary domain and catalytic site have identified by or yet has not yet a of the prodomain. Although the structure is not yet for ADAMTS zymogens, we that the we have be in the structure of the zymogen and the role of the prodomain. for the ADAMTS-1 also K. R. E. and R. for their of and Apte for of this

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