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J. Biol. Chem., Vol. 281, Issue 27, 18626-18637, July 7, 2006

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The Hemopexin and O-Glycosylated Domains Tune Gelatinase B/MMP-9 Bioavailability via Inhibition and Binding to Cargo Receptors^*

Philippe E. Van den Steen¹, Ilse Van Aelst, Vibeke Hvidberg, Helene Piccard, Pierre Fiten, Christian Jacobsen, Soren K. Moestrup, Simon Fry^¶, Louise Royle^¶, Mark R. Wormald^¶, Russell Wallis^||, Pauline M. Rudd^¶, Raymond A. Dwek^¶, and Ghislain Opdenakker²

From the Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, B-3000, Belgium, the Department of Medical Biochemistry, University of Aarhus, Denmark, the ^¶Oxford Glycobiology Institute, University of Oxford, OX1 3QU, United Kingdom, and the ^||MRC Immunochemistry Unit, Department of Biochemistry, University of Oxford, OX1 3QU, United Kingdom, and Department of Infection, Immunity and Inflammation, University of Leicester, LE1 9HN United Kingdom

Gelatinase B/matrix metalloproteinase-9 (MMP-9), a key regulator and effector of immunity, contains a C-terminal hemopexin domain preceded by a unique linker sequence of 64 amino acid residues. This linker sequence is demonstrated to be an extensively O-glycosylated (OG) domain with a compact three-dimensional structure. The OG and hemopexin domains have no influence on the cleavage efficiency of MMP-9 substrates. In contrast, the hemopexin domain contains a binding site for the cargo receptor low density lipoprotein receptor-related protein-1 (LRP-1). Furthermore, megalin/LRP-2 is identified as a new functional receptor for the hemopexin domain of MMP-9, able to mediate the endocytosis and catabolism of the enzyme. The OG domain is required to correctly orient the hemopexin domain for inhibition by TIMP-1 and internalization by LRP-1 and megalin. Therefore, the OG and hemopexin domains down-regulate the bioavailability of active MMP-9 and the interactions with the cargo receptors are proposed to be the original function of hemopexin domains in MMPs.

Received for publication, November 16, 2005 , and in revised form, April 21, 2006.

^* This study was supported by the Geconcerteerde OnderzoeksActies 2002-2006 and 2006-2010, the National Fund for Scientific Research (F.W.O.-Vlaanderen), the Centre of Excellence EF/05/015, the Charcot Foundation, and the Federation against Cancer (Belgium). This work was also supported by funding from the Oxford Glycobiology Institute. 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 A postdoctoral fellow of the F.W.O.-Vlaanderen.

² To whom correspondence should be addressed: Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium. Tel.: 32-16-337341; Fax: 32-16-337340; E-mail: ghislain.opdenakker{at}rega.kuleuven.be.

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