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Lysyl oxidase–like 2 (LOXL2)–mediated cross-linking of tropoelastin

Lysyl oxidases (LOXs) play a central role in extracellular matrix remodeling during development and tumor growth and fibrosis through cross-linking of collagens and elastin. We have limited knowledge of the structure and substrate specificity of these secreted enzymes. LOXs share a conserved C-termi...

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Autores principales: Schmelzer, Christian E. H., Heinz, Andrea, Troilo, Helen, Lockhart-Cairns, Michael P., Jowitt, Thomas A., Marchand, Marion F., Bidault, Laurent, Bignon, Marine, Hedtke, Tobias, Barret, Alain, McConnell, James C., Sherratt, Michael J., Germain, Stéphane, Hulmes, David J. S., Baldock, Clair, Muller, Laurent
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Federation of American Societies for Experimental Biology 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629125/
https://www.ncbi.nlm.nih.gov/pubmed/30676771
http://dx.doi.org/10.1096/fj.201801860RR
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author Schmelzer, Christian E. H.
Heinz, Andrea
Troilo, Helen
Lockhart-Cairns, Michael P.
Jowitt, Thomas A.
Marchand, Marion F.
Bidault, Laurent
Bignon, Marine
Hedtke, Tobias
Barret, Alain
McConnell, James C.
Sherratt, Michael J.
Germain, Stéphane
Hulmes, David J. S.
Baldock, Clair
Muller, Laurent
author_facet Schmelzer, Christian E. H.
Heinz, Andrea
Troilo, Helen
Lockhart-Cairns, Michael P.
Jowitt, Thomas A.
Marchand, Marion F.
Bidault, Laurent
Bignon, Marine
Hedtke, Tobias
Barret, Alain
McConnell, James C.
Sherratt, Michael J.
Germain, Stéphane
Hulmes, David J. S.
Baldock, Clair
Muller, Laurent
author_sort Schmelzer, Christian E. H.
collection PubMed
description Lysyl oxidases (LOXs) play a central role in extracellular matrix remodeling during development and tumor growth and fibrosis through cross-linking of collagens and elastin. We have limited knowledge of the structure and substrate specificity of these secreted enzymes. LOXs share a conserved C-terminal catalytic domain but differ in their N-terminal region, which is composed of 4 repeats of scavenger receptor cysteine-rich (SRCR) domains in LOX-like (LOXL) 2. We investigated by X-ray scattering and electron microscopy the low-resolution structure of the full-length enzyme and the structure of a shorter form lacking the catalytic domain. Our data demonstrate that LOXL2 has a rod-like structure with a stalk composed of the SRCR domains and the catalytic domain at its tip. We detected direct interaction between LOXL2 and tropoelastin (TE) and also LOXL2-mediated deamination of TE. Using proteomics, we identified several allysines together with cross-linked TE peptides. The elastin-like material generated was resistant to trypsin proteolysis and displayed mechanical properties similar to mature elastin. Finally, we detected the codistribution of LOXL2 and elastin in the vascular wall. Altogether, these data suggest that LOXL2 could participate in elastogenesis in vivo and could be used as a means of cross-linking TE in vitro for biomimetic and cell-compatible tissue engineering purposes.—Schmelzer, C. E. H., Heinz, A., Troilo, H., Lockhart-Cairns, M.-P., Jowitt, T. A., Marchand, M. F., Bidault, L., Bignon, M., Hedtke, T., Barret, A., McConnell, J. C., Sherratt, M. J., Germain, S., Hulmes, D. J. S., Baldock, C., Muller, L. Lysyl oxidase–like 2 (LOXL2)–mediated cross-linking of tropoelastin.
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spelling pubmed-66291252019-07-18 Lysyl oxidase–like 2 (LOXL2)–mediated cross-linking of tropoelastin Schmelzer, Christian E. H. Heinz, Andrea Troilo, Helen Lockhart-Cairns, Michael P. Jowitt, Thomas A. Marchand, Marion F. Bidault, Laurent Bignon, Marine Hedtke, Tobias Barret, Alain McConnell, James C. Sherratt, Michael J. Germain, Stéphane Hulmes, David J. S. Baldock, Clair Muller, Laurent FASEB J Research Lysyl oxidases (LOXs) play a central role in extracellular matrix remodeling during development and tumor growth and fibrosis through cross-linking of collagens and elastin. We have limited knowledge of the structure and substrate specificity of these secreted enzymes. LOXs share a conserved C-terminal catalytic domain but differ in their N-terminal region, which is composed of 4 repeats of scavenger receptor cysteine-rich (SRCR) domains in LOX-like (LOXL) 2. We investigated by X-ray scattering and electron microscopy the low-resolution structure of the full-length enzyme and the structure of a shorter form lacking the catalytic domain. Our data demonstrate that LOXL2 has a rod-like structure with a stalk composed of the SRCR domains and the catalytic domain at its tip. We detected direct interaction between LOXL2 and tropoelastin (TE) and also LOXL2-mediated deamination of TE. Using proteomics, we identified several allysines together with cross-linked TE peptides. The elastin-like material generated was resistant to trypsin proteolysis and displayed mechanical properties similar to mature elastin. Finally, we detected the codistribution of LOXL2 and elastin in the vascular wall. Altogether, these data suggest that LOXL2 could participate in elastogenesis in vivo and could be used as a means of cross-linking TE in vitro for biomimetic and cell-compatible tissue engineering purposes.—Schmelzer, C. E. H., Heinz, A., Troilo, H., Lockhart-Cairns, M.-P., Jowitt, T. A., Marchand, M. F., Bidault, L., Bignon, M., Hedtke, T., Barret, A., McConnell, J. C., Sherratt, M. J., Germain, S., Hulmes, D. J. S., Baldock, C., Muller, L. Lysyl oxidase–like 2 (LOXL2)–mediated cross-linking of tropoelastin. Federation of American Societies for Experimental Biology 2019-04 2019-01-24 /pmc/articles/PMC6629125/ /pubmed/30676771 http://dx.doi.org/10.1096/fj.201801860RR Text en © FASEB http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Schmelzer, Christian E. H.
Heinz, Andrea
Troilo, Helen
Lockhart-Cairns, Michael P.
Jowitt, Thomas A.
Marchand, Marion F.
Bidault, Laurent
Bignon, Marine
Hedtke, Tobias
Barret, Alain
McConnell, James C.
Sherratt, Michael J.
Germain, Stéphane
Hulmes, David J. S.
Baldock, Clair
Muller, Laurent
Lysyl oxidase–like 2 (LOXL2)–mediated cross-linking of tropoelastin
title Lysyl oxidase–like 2 (LOXL2)–mediated cross-linking of tropoelastin
title_full Lysyl oxidase–like 2 (LOXL2)–mediated cross-linking of tropoelastin
title_fullStr Lysyl oxidase–like 2 (LOXL2)–mediated cross-linking of tropoelastin
title_full_unstemmed Lysyl oxidase–like 2 (LOXL2)–mediated cross-linking of tropoelastin
title_short Lysyl oxidase–like 2 (LOXL2)–mediated cross-linking of tropoelastin
title_sort lysyl oxidase–like 2 (loxl2)–mediated cross-linking of tropoelastin
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629125/
https://www.ncbi.nlm.nih.gov/pubmed/30676771
http://dx.doi.org/10.1096/fj.201801860RR
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