Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible protein with numerous partners

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...

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Bibliographic Details
Published in:Scientific reports 2018-08, Vol.8 (1), p.11768-16, Article 11768
Main Authors: Vallet, Sylvain D., Miele, Adriana E., Uciechowska-Kaczmarzyk, Urszula, Liwo, Adam, Duclos, Bertrand, Samsonov, Sergey A., Ricard-Blum, Sylvie
Format: Article
Language:English
Subjects:
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Biochemistry
Biochemistry, Molecular Biology
Circular dichroism
Collagen (type I)
Cross-linking
Deamination
Elastin
Epidermal growth factor
Extracellular matrix
Glycosaminoglycans
Heparan sulfate
Humanities and Social Sciences
Hyaluronic acid
Life Sciences
Light scattering
Lysine
Lysyl oxidase
Matrix metalloproteinase
Membrane proteins
Metalloproteinase
multidisciplinary
Proteins
Proteolysis
Proteolytic enzymes
Science
Science (multidisciplinary)
Signal transduction
Transglutaminase 2
X-ray scattering
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Summary: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 (D max : 11.7 nm, R g : 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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-30190-6