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Originally published In Press as doi:10.1074/jbc.M909383199 on April 4, 2000

J. Biol. Chem., Vol. 275, Issue 24, 18566-18573, June 16, 2000
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Sites of Aggrecan Cleavage by Recombinant Human Aggrecanase-1 (ADAMTS-4)*

Micky D. TortorellaDagger §, Michael PrattaDagger , Rui-Qin LiuDagger , Julian AustinDagger , O. Harold Ross, Ilgar Abbaszade, Tim Burn, and Elizabeth ArnerDagger

From the Departments of Dagger  Inflammatory Diseases Research and  Applied Biotechnology, DuPont Pharmaceuticals Company, Wilmington, Delaware 19880-0400

Aggrecan, the major proteoglycan of cartilage that provides its mechanical properties of compressibility and elasticity, is one of the first matrix components to undergo measurable loss in arthritic diseases. Two major sites of proteolytic cleavage have been identified within the interglobular domain (IGD) of the aggrecan core protein, one between amino acids Asn341-Phe342 which is cleaved by matrix metalloproteinases and the other between Glu373-Ala374 that is attributed to aggrecanase. Although several potential aggrecanase-sensitive sites had been identified within the COOH terminus of aggrecan, demonstration that aggrecanase cleaved at these sites awaited isolation and purification of this protease. We have recently cloned human aggrecanase-1 (ADAMTS-4) (Tortorella, 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, M. C., Jr., Hollis, G. F., Newton, R. C., Magolda, R. L., Trzaskos, J. M., and Arner, E. C. (1999) Science 284, 1664-1666) and herein demonstrate that in addition to cleavage at the Glu373-Ala374 bond, this protease cleaves at four sites within the chondroitin-sulfate rich region of the aggrecan core protein, between G2 and G3 globular domains. Importantly, we show that this cleavage occurs more efficiently than cleavage within the IGD at the Glu373-Ala374 bond. Cleavage occurred preferentially at the KEEE1667-1668GLGS bond to produce both a 140-kDa COOH-terminal fragment and a 375-kDa fragment that retains an intact G1. Cleavage also occurred at the GELE1480-1481GRGT bond to produce a 55-kDa COOH-terminal fragment and a G1-containing fragment of 320 kDa. Cleavage of this 320-kDa fragment within the IGD at the Glu373-Ala374 bond then occurred to release the 250-kDa BC-3-reactive fragment from the G1 domain. The 140-kDa GLGS-reactive fragment resulting from the preferential cleavage was further processed at two additional cleavage sites, at TAQE1771-1772AGEG and at VSQE1871-1872LGQR resulting in the formation of a 98-kDa fragment with an intact G3 domain and two small fragments of ~20 kDa. These data elucidate the sites and efficiency of cleavage during aggrecan degradation by aggrecanase and suggest potential tools for monitoring aggrecan cleavage in arthritis.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: The Kennedy Institute of Rheumatology, 1 Aspenlea Rd., Hammersmith, London W6 8LH, United Kingdom. Tel.: 44-208-383-4446; Fax: 44-181-383-4499; E-mail: tortormd@aol.com.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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