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

Sylvain D. Vallet , Adriana E. Miele , Urszula Uciechowska-Kaczmarzyk , Józef Adam Liwo , Bertrand Duclos , Sergey Samsonov , Sylvie Ricard-Blum

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 (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.
Author Sylvain D. Vallet
Sylvain D. Vallet,,
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, Adriana E. Miele
Adriana E. Miele,,
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, Urszula Uciechowska-Kaczmarzyk (FCh / DTCh / LMM)
Urszula Uciechowska-Kaczmarzyk,,
- Laboratory of Molecular Modeling
, Józef Adam Liwo (FCh / DTCh / LMM)
Józef Adam Liwo,,
- Laboratory of Molecular Modeling
, Bertrand Duclos
Bertrand Duclos,,
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, Sergey Samsonov (FCh / DTCh / LMM)
Sergey Samsonov,,
- Laboratory of Molecular Modeling
, Sylvie Ricard-Blum
Sylvie Ricard-Blum,,
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Journal seriesScientific Reports, ISSN 2045-2322, (A 40 pkt)
Issue year2018
Vol8
Pages1-16
Publication size in sheets0.75
DOIDOI:10.1038/s41598-018-30190-6
URL https://www.nature.com/articles/s41598-018-30190-6.pdf
Languageen angielski
LicenseJournal (articles only); published final; Uznanie Autorstwa (CC-BY); with publication
Score (nominal)40
ScoreMinisterial score = 40.0, 31-08-2018, ArticleFromJournal
Ministerial score (2013-2016) = 40.0, 31-08-2018, ArticleFromJournal
Publication indicators WoS Impact Factor: 2016 = 4.259 (2) - 2016=4.847 (5)
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