Hemopexin domains as multifunctional liganding modules in matrix metalloproteinases and other proteins

Abstract

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.

A 17-residue Sequence from the Matrix Metalloproteinase-9 (MMP-9) Hemopexin Domain Binds α4β1 Integrin and Inhibits MMP-9-induced Functions in Chronic Lymphocytic Leukemia B Cells

“…B-CLL cell interaction with isolated PEX9 thus appears to differ from binding to (pro)MMP-9, which we previously showed (and confirmed here) to require ␣4␤1 and CD44v engagement (12). Indeed, CD44H is a well known receptor for MMP-9 in many cell types (14,33,34), and a recent study using MMP-9-transfected COS-1 cells has located a CD44 binding region in blade I of the MMP-9 hemopexin domain (16). Our present results show that CD44 was not involved in B-CLL cell adhesion to GST-PEX9 and that both proteins did not colocalize at the cell surface.…”

“…Given the lower homology among MMP hemopexin domains compared with catalytic domains (14), targeting PEX9, in particular its interaction with cell surface receptors, may be a useful and more specific approach to prevent B-CLL cell dissemination and survival. These strategies are already in progress in other cell systems.…”

“…6A shows that P3a, but not the control P3am, inhibited primary B-CLL and MEC-1 cell adhesion to PEX9 in a dose-dependent Table 2). B, BCECF-AM-labeled primary B-CLL cells (patients 8,14,19) (Fig. 6B).…”

Matrix metalloproteinases in head and neck cancer: current perspectives

“…104 The PEX domain of MMPs is now considered to be responsible for their noncatalytic activity, as it is capable of interacting with receptors, inhibitors, and substrates. [105][106][107] For example, the PEX domain interacts with cellsurface receptors, including LRP1 and megalin/LRP2, 108,109 as well as with inhibitors, such as TIMP1 110 and TIMP3. 111 Besides receptor and inhibitor binding, the PEX region also interacts with substrates, including gelatin, collagen types I and IV, elastin, and fibrinogen.…”

Identification of genes potentially involved in bone metastasis by genome-wide gene expression profile analysis of non-small cell lung cancer in mice

“…It is remarkable that there are hundreds of proteins, including MMPs, containing one or several motifs that structurally and functionally resemble parts of the HPX protein (review in ref. 44). A latest report shows that small-molecule compounds that selectively target the hemopexin domain of MMP-9 can control tumor growth and inhibit lung metastasis in breast cancer xenograft model in mice (45).…”