Cloning and characterization of ADAMTS11, an aggrecanase from the ADAMTS family
| Autor: | Carl P. Decicco, M.C. Hillman, Dawn Ellis, Henry J. George, Ronald L. Magolda, Rui-Qin Liu, O. Harold Ross, John Link, Micky D. Tortorella, James M. Trzaskos, J. L. Duke, Jeannine M. Hollis, Gregory Hollis, Michael A. Pratta, Robert C. Bruckner, Fude Yang, Stuart A. Rosenfeld, Timothy Burn, Robert A. Copeland, Elizabeth C. Arner, Hideaki Nagase, Richard Wynn, Yoshifumi Itoh, Barbara H. Wiswall, Ilgar Abbaszade, Kathleen Murphy, Robert C. Newton |
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| Rok vydání: | 1999 |
| Předmět: |
DNA
Complementary Molecular Sequence Data Biochemistry Endopeptidases Animals Humans Amino Acid Sequence Cloning Molecular Molecular Biology Aggrecan Integrin binding Aggrecanase Base Sequence Sequence Homology Amino Acid Chemistry ADAMTS Metalloendopeptidases Cell Biology ADAMTS4 Protein Recombinant Proteins ADAM Proteins ADAMTS4 Extracellular matrix binding Cattle ADAMTS5 Protein ADAMTS Proteins |
| Zdroj: | The Journal of biological chemistry. 274(33) |
| ISSN: | 0021-9258 |
| Popis: | Aggrecan is responsible for the mechanical properties of cartilage. One of the earliest changes observed in arthritis is the depletion of cartilage aggrecan due to increased proteolytic cleavage within the interglobular domain. Two major sites of cleavage have been identified in this region at Asn(341)-Phe(342) and Glu(373)-Ala(374). While several matrix metalloproteinases have been shown to cleave at Asn(341)-Phe(342), an as yet unidentified protein termed "aggrecanase" is responsible for cleavage at Glu(373)-Ala(374) and is hypothesized to play a pivotal role in cartilage damage. We have identified and cloned a novel disintegrin metalloproteinase with thrombospondin motifs that possesses aggrecanase activity, ADAMTS11 (aggrecanase-2), which has extensive homology to ADAMTS4 (aggrecanase-1) and the inflammation-associated gene ADAMTS1. ADAMTS11 possesses a number of conserved domains that have been shown to play a role in integrin binding, cell-cell interactions, and extracellular matrix binding. We have expressed recombinant human ADAMTS11 in insect cells and shown that it cleaves aggrecan at the Glu(373)-Ala(374) site, with the cleavage pattern and inhibitor profile being indistinguishable from that observed with native aggrecanase. A comparison of the structure and expression patterns of ADAMTS11, ADAMTS4, and ADAMTS1 is also described. Our findings will facilitate the study of the mechanisms of cartilage degradation and provide targets to search for effective inhibitors of cartilage depletion in arthritic disease. |
| Databáze: | OpenAIRE |
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