The hemopexin and O-glycosylated domains tune gelatinase B/MMP-9 bioavailability via inhibition and binding to cargo receptors |
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Authors: | Van den Steen Philippe E Van Aelst Ilse Hvidberg Vibeke Piccard Helene Fiten Pierre Jacobsen Christian Moestrup Soren K Fry Simon Royle Louise Wormald Mark R Wallis Russell Rudd Pauline M Dwek Raymond A Opdenakker Ghislain |
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Affiliation: | Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, B-3000, Belgium. |
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Abstract: | 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 approximately 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. |
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