Abstract
Lysyl oxidase (LOX) catalyzes the oxidative deamination of lysine and hydroxylysine residues in collagens and elastin, which is the first step of the cross-linking of these extracellular matrix proteins. It is secreted as a proenzyme activated by bone morphogenetic protein-1, which releases the LOX catalytic domain and its bioactive N-terminal propeptide. We characterized the recombinant human propeptide by circular dichroism, dynamic light scattering, and small-angle X-ray scattering (SAXS), and showed that it is elongated, monomeric, disordered and flexible (Dmax: 11.7 nm, Rg: 3.7 nm). We generated 3D models of the propeptide by coarse-grained molecular dynamics simulations restrained by SAXS data, which were used for docking experiments. Furthermore, we have identified 17 new binding partners of the propeptide by label-free assays. They include four glycosaminoglycans (hyaluronan, chondroitin, dermatan and heparan sulfate), collagen I, cross-linking and proteolytic enzymes (lysyl oxidase-like 2, transglutaminase-2, matrix metalloproteinase-2), a proteoglycan (fibromodulin), one growth factor (Epidermal Growth Factor, EGF), and one membrane protein (tumor endothelial marker-8). This suggests new roles for the propeptide in EGF signaling pathway.
Highlights
Lysyl oxidase (LOX), a copper amine oxidase, catalyzes the oxidative deamination of lysine and hydroxylysine residues in collagens and elastin, which is the first step of the covalent cross-linking of these extracellular matrix (ECM) proteins[1]
We report here the characterization of recombinant human LOX-PP by circular dichroism, dynamic light scattering (DLS), and small-angle X-ray scattering (SAXS), which showed that human LOX-PP is an elongated, monomeric, flexible, protein enriched in intrinsic disorder
We have explored the ability of LOX-PP to interact with the ECM, and we have identified 17 new partners of LOX-PP, including four glycosaminoglycans (GAGs, chondroitin sulfate, dermatan sulfate, heparan sulfate, and hyaluronan), collagen I, cross-linking and proteolytic enzymes, one proteoglycan, one growth factor (Epidermal Growth Factor, EGF), and one membrane protein (Tumor Endothelial Marker-8, TEM-8, known as anthrax receptor-1)
Summary
Lysyl oxidase (LOX), a copper amine oxidase, catalyzes the oxidative deamination of lysine and hydroxylysine residues in collagens and elastin, which is the first step of the covalent cross-linking of these extracellular matrix (ECM) proteins[1]. We have explored the ability of LOX-PP to interact with the ECM, and we have identified 17 new partners of LOX-PP, including four glycosaminoglycans (GAGs, chondroitin sulfate, dermatan sulfate, heparan sulfate, and hyaluronan), collagen I, cross-linking and proteolytic enzymes (lysyl oxidase-like 2, transglutaminase-2, matrix metalloproteinase-2), one proteoglycan (fibromodulin), one growth factor (Epidermal Growth Factor, EGF), and one membrane protein (Tumor Endothelial Marker-8, TEM-8, known as anthrax receptor-1). This suggests new roles for the propeptide in ECM assembly and cross-linking, cell-matrix adhesion, and in the regulation of EGF signaling pathways
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