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.
Journal of Biological Chemistry, 2006, Vol 281, Issue 27, p. 18626-37
Binding Sites; Catalytic Domain; Down-Regulation; Glycosylation; Hemopexin; Humans; Low Density Lipoprotein Receptor-Related Protein-1; Low Density Lipoprotein Receptor-Related Protein-2; Matrix Metalloproteinase 9; Models, Molecular; Protein Binding; Protein Structure, Tertiary; Recombinant Proteins; Structure-Activity Relationship; Tissue Inhibitor of Metalloproteinase-1