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

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.

Megalin is a receptor for apolipoprotein M, and kidney-specific megalin-deficiency confers urinary excretion of apolipoprotein M.

Apolipoprotein (apo) M is a novel apolipoprotein belonging to the lipocalin protein superfamily, i.e. proteins binding small lipophilic compounds.

Identification of the receptor scavenging hemopexin-heme complexes.

Heme released from heme-binding proteins on internal hemorrhage, hemolysis, myolysis, or other cell damage is highly toxic due to oxidative and proinflammatory effects. Complex formation with hemopexin, the high-affinity heme-binding protein in plasma and cerebrospinal fluid, dampens these effects and is suggested to facilitate cellular heme metabolism. Using a ligand-affinity approach, we purified the human hemopexin-heme receptor and identified it as the low-density lipoprotein receptor-related protein (LRP)/CD91, a receptor expressed in several cell types including macrophages, hepatocytes, neurons, and syncytiotrophoblasts.

The endocytic receptor megalin binds the iron transporting neutrophil-gelatinase-associated lipocalin with high affinity and mediates its cellular uptake.

Neutrophil-gelatinase-associated lipocalin (NGAL) is a prominent protein of specific granules of human neutrophils also synthesized by epithelial cells during inflammation. NGAL binds bacterial siderophores preventing bacteria from retrieving iron from this source. Also, NGAL may be important in delivering iron to cells during formation of the tubular epithelial cells of the primordial kidney.