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J. Biol. Chem., Vol. 280, Issue 29, 27044-27055, July 22, 2005

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Characterization of the Interaction between Tumor Necrosis Factor-stimulated Gene-6 and Heparin

IMPLICATIONS FOR THE INHIBITION OF PLASMIN IN EXTRACELLULAR MATRIX MICROENVIRONMENTS^*

David J. Mahoney, Barbara Mulloy¶, Mark J. Forster¶, Charles D. Blundell||**, Eric Fries, Caroline M Milner, Supported by a Nuffield Foundation Oliver Bird Fellowship (RHE/00045/G), and Anthony J. Day¶¶

From the Medical Research Council Immunochemistry Unit and the ^||Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom, the ^¶National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar, EN6 3QG, Hertfordshire, United Kingdom, and the Department of Medical Biochemistry and Microbiology, Uppsala University, S-751 23 Uppsala, Sweden

TSG-6, the secreted product of tumor necrosis factor-stimulated gene-6, is not constitutively expressed but is up-regulated in various cell-types during inflammatory and inflammation-like processes. The mature protein is comprised largely of contiguous Link and CUB modules, the former binding several matrix components such as hyaluronan (HA) and aggrecan. Here we show that this domain can also associate with the glycosaminoglycan heparin/heparan sulfate. Docking predictions and site-directed mutagenesis demonstrate that this occurs at a site distinct from the HA binding surface and is likely to involve extensive electrostatic contacts. Despite these glycosaminoglycans binding to non-overlapping sites on the Link module, the interaction of heparin can inhibit subsequent binding to HA, and it is possible that this occurs via an allosteric mechanism. We also show that heparin can modify another property of the Link module, i.e. its potentiation of the anti-plasmin activity of inter--inhibitor (II). Experiments using the purified components of II indicate that TSG-6 only binds to the bikunin chain and that this is at a site on the Link module that overlaps the HA binding surface. The association of heparin with the Link module significantly increases the anti-plasmin activity of the TSG-6·II complex. Changes in plasmin activity have been observed previously at sites of TSG-6 expression, and the results presented here suggest that TSG-6 is likely to contribute to matrix remodeling, at least in part, through down-regulation of the protease network, especially in locations containing heparin/heparan sulfate proteoglycans. The differential effects of HA and heparin on TSG-6 function provide a mechanism for its regulation and functional partitioning in particular tissue microenvironments.

Received for publication, February 23, 2005 , and in revised form, May 2, 2005.

^* This work was supported in part by the United Kingdom Medical Research Council and Arthritis Research Campaign (ARC). 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.

Supported by the ARC (Grants M0621, M0625, 16119, and 16539).

^** Supported by an ARC PhD studentship (Grant D0569).

To whom correspondence may be addressed. Tel.: 44-1865-275348; Fax: 44-1865-275729; E-mail: caroline.milner{at}bioch.ox.ac.uk. ¶¶ To whom correspondence may be addressed. Tel.: 44-1865-275349; Fax: 44-1865-275729; E-mail: tony.day{at}bioch.ox.ac.uk.

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