β-Hematin Interaction with the Hemopexin Domain of Gelatinase B/MMP-9 Provokes Autocatalytic Processing of the Propeptide, Thereby Priming Activation by MMP-3

Abstract

Gelatinase B or matrix metalloproteinase-9 is involved in inflammation and in autoimmune and vascular diseases. In contrast to the constitutive and homeostatic matrix metalloproteinase-2, matrix metalloproteinase-9 is an inducible enzyme. Furthermore, it needs tight regulation, and a major control mechanism of its enzymatic activity is the activation of the latent enzyme by proteolysis of the 87 residue propeptide. Activated matrix metalloproteinase-9 is detected in many vascular or hematological disease states, including in an experimental model for cerebral malaria with Plasmodium berghei ANKA. However, insight into its activation mechanism is incomplete. In view of the association with hemorrhagic and hemolytic diseases, it was studied whether and how hemoglobin and its derivatives might activate pro-matrix metalloproteinase-9. Incubation of matrix metalloproteinase-9 with hemin or beta-hematin, the core constituent of hemozoin or malaria pigment, leads to differential autocatalysis of the propeptide, mediated by allosteric interaction with the hemopexin domain. The cleavage catalyzed by beta-hematin coincides with the first cleavage by stromelysin-1/matrix metalloproteinase-3, and preincubation of matrix metalloproteinase-9 with beta-hematin enhances the activation rate by matrix metalloproteinase-3 at least 6-fold. These findings suggest that reduction of hemorrhage and hemolysis might prevent matrix metalloproteinase-9-mediated inflammatory and vascular damages.

Functional Characterization of Anopheles Matrix Metalloprotease 1 Reveals Its Agonistic Role during Sporogonic Development of Malaria Parasites

“…Overproduced NO during microbial infections is speculated to activate secreted pro-MMPs by the chemical modification of the "cysteine switch" (60,61); during West Nile virus (62) and Plasmodium falciparum (63) infection, expression of active MMP-9 was shown to increase significantly. In the case of Plasmodium infection, in vitro studies suggest a mechanism through which hemozoin provokes autocatalytic processing of the propeptide (64). It would be interesting to determine whether plasmodial proteases expressed in the sexual stages of the parasite (65) could interact with host MMPs, in this case latent S-MMP1, and mediate its activation directly or indirectly.…”

Neutrophil MMP-9 Proenzyme, Unencumbered by TIMP-1, Undergoes Efficient Activation in Vivo and Catalytically Induces Angiogenesis via a Basic Fibroblast Growth Factor (FGF-2)/FGFR-2 Pathway

“…Proteolytic cleavage of matrix components sequestering FGF-2 by active MMP-9 is also consistent with the indicated requirement of the hemopexin domain of MMP-9 for angiogenic induction. This C-terminal non-catalytic domain, often referred to as PEX, can be involved in directing MMP-9 to specific components of the ECM and enhancing the degradative activity of the enzyme to those PEX-directed substrates (37,40,42,43). Furthermore, the peak of MMP-9-mediated enhancement of FGF-2 occurs at ϳ24 h, i.e.…”

Crystal Structure and Functional Insights of Hemopexin Fold Protein from Grass Pea

“…Also, binding of heme competes with the LS-24 dimerization, implying that the protein binds to heme in the monomeric state. Other hemopexin domains lacking the architecture of mammalian serum hemopexin are also known to show heme-binding ability (Geurts et al, 2008).…”