The hemopexin and O-glycosylated domains tune gelatinase B/MMP-9 bioavailability via inhibition and binding to cargo receptors - PubMed (original) (raw)

. 2006 Jul 7;281(27):18626-37.

doi: 10.1074/jbc.M512308200. Epub 2006 May 3.

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, Ghislain Opdenakker

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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 Steen et al. J Biol Chem. 2006.

Free article

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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