The hemopexin and O-glycosylated domains tune gelatinase B/MMP-9 bioavailability via inhibition and binding to cargo receptors.

Journal article

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.

Authors: Van den Steen, P; Van Aelst, I; Hvidberg, V; Piccard, H; Fiten, P

• Publication status: Published
• Journal: Journal of biological chemistry
• Volume: 281
• Issue: 27
• Pages: 18626-18637
• Publication date: 2006-07-01
• DOI: 10.1074/jbc.m512308200
• EISSN: 1083-351X
• ISSN: 0021-9258
• Language: English
• Keywords: Glycosylation; Down-Regulation; Humans; Protein Binding; Tissue Inhibitor of Metalloproteinase-1; Recombinant Proteins; Structure-Activity Relationship; Protein Structure, Tertiary; Low Density Lipoprotein Receptor-Related Protein-2; Binding Sites; Catalytic Domain; Low Density Lipoprotein Receptor-Related Protein-1; Models, Molecular; Hemopexin; Matrix Metalloproteinase 9