No 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 ϳ64 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.

The heme-binding hemopexin consists of two, four-bladed propeller domains connected by a linker region. Hemopexin domains are found in different species on the phylogenetic tree and in the human species represented in hemopexin, matrix metalloproteinases (MMPs), vitronectin, and products of the proteoglycan 4 gene. Hemopexin and hemopexin domains of human proteins fulfill functions in activation of MMPs, inhibition of MMPs, dimerization, binding of substrates or ligands, cleavage of substrates, and endocytosis by low-density lipoprotein receptor-related protein-1 (LRP-1; CD91) and LRP-2 (megalin, GP330). Insights into the structures and functions of hemopexin (domains) form the basis for positive or negative interference with the formation of molecular complexes and hence, might be exploited therapeutically in inflammation, cancer, and wound healing.