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J. Biol. Chem., Vol. 280, Issue 38, 32877-32882, September 23, 2005

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Reactive Site Mutations in Tissue Inhibitor of Metalloproteinase-3 Disrupt Inhibition of Matrix Metalloproteinases but Not Tumor Necrosis Factor--converting Enzyme^*

Shuo Wei, Masahide Kashiwagi, Smitha Kota, Zhihong Xie, Hideaki Nagase, and Keith Brew1

From the Department of Biomedical Science, Florida Atlantic University, Boca Raton, Florida 33431 and the Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, 1 Aspenlea Road, Hammersmith, London W6 8LH, United Kingdom

Tissue inhibitor of metalloproteinase-3 (TIMP-3) is a dual inhibitor of the matrix metalloproteinases (MMPs) and some adamalysins, two families of extracellular and cell surface metalloproteinases that function in extracellular matrix turnover and the shedding of cell surface proteins. The mechanism of inhibition of MMPs by TIMPs has been well characterized, and since the catalytic domains of MMPs and adamalysins are homologous, it was assumed that the interaction of TIMP-3 with adamalysins is closely similar. Here we report that the inhibition of the extracellular region of ADAM-17 (tumor necrosis factor -converting enzyme (TACE)) by the inhibitory domain of TIMP-3 (N-TIMP-3) shows positive cooperativity. Also, mutations in the core of the MMP interaction surface of N-TIMP-3 dramatically reduce the binding affinity for MMPs but have little effect on the inhibitory activity for TACE. These results suggest that the mechanism of inhibition of ADAM-17 by TIMP-3 may be distinct from that for MMPs. The mutant proteins are also effective inhibitors of tumor necrosis factor (TNF-) release from phorbol ester-stimulated cells, indicating that they provide a lead for engineering TACE-specific inhibitors that may reduce side effects arising from MMP inhibition and are possibly useful for treatment of diseases associated with excessive TNF- levels such as rheumatoid arthritis.

Received for publication, May 25, 2005 , and in revised form, June 15, 2005.

^* This work was supported by Grant AR40994 from the National Institutes of Health (to K. B.) and Wellcome Trust Grant 057508 (to H. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biomedical Sciences, FL Atlantic University, Boca Raton, FL 33431. Tel.: 561-297-0416; Fax: 561-297-2221; E-mail: kbrew{at}fau.edu.

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