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.

Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible protein with numerous partners / Vallet, Sylvain D.; Miele, Adriana E.; Uciechowska-Kaczmarzyk, Urszula; Liwo, Adam; Duclos, Bertrand; Samsonov, Sergey A.; Ricard-Blum, Sylvie. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 8:1(2018), pp. 11768-11783. [10.1038/s41598-018-30190-6]

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

Adriana E. Miele
Secondo
Investigation
;
2018

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.
2018
extracellular matrix; SAXS; intrisically disordered proteins; molecular dynamics
01 Pubblicazione su rivista::01a Articolo in rivista
Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible protein with numerous partners / Vallet, Sylvain D.; Miele, Adriana E.; Uciechowska-Kaczmarzyk, Urszula; Liwo, Adam; Duclos, Bertrand; Samsonov, Sergey A.; Ricard-Blum, Sylvie. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 8:1(2018), pp. 11768-11783. [10.1038/s41598-018-30190-6]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1161978
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