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

DOI: 10.1096/fj.201801860RR DOI Help

Authors: Christian E. H. Schmelzer (Fraunhofer Institute for Microstructure of Materials and Systems (IMWS); Martin Luther University Halle-Wittenberg) , Andrea Heinz (Fraunhofer Institute for Microstructure of Materials and Systems (IMWS); Martin Luther University Halle-Wittenberg) , Helen Troilo (Wellcome Trust Centre for Cell-Matrix Research, University of Manchester) , Michael P. Lockhart-cairns (Wellcome Trust Centre for Cell-Matrix Research, University of Manchester) , Thomas A. Jowitt (Wellcome Trust Centre for Cell-Matrix Research, University of Manchester) , Marion F. Marchand (CNRS, INSERM, PSL Research University) , Laurent Bidault (CNRS, INSERM, PSL Research University) , Marine Bignon (CNRS, INSERM, PSL Research University) , Tobias Hedtke (Fraunhofer Institute for Microstructure of Materials and Systems (IMWS); Martin Luther University Halle-Wittenberg) , Alain Barret (CNRS, INSERM, PSL Research University) , James C. Mcconnell (University of Manchester) , Michael J. Sherratt (University of Manchester) , Stéphane Germain (CNRS, INSERM, PSL Research University) , David J. S. Hulmes (CNRS, INSERM, PSL Research University) , Clair Baldock (CNRS, INSERM, PSL Research University) , Laurent Muller (CNRS, INSERM, PSL Research University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: The Faseb Journal

State: Published (Approved)
Published: January 2019
Diamond Proposal Number(s): 1783

Abstract: 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.

Journal Keywords: matrix remodeling; elastin; protein structure; SAXS; proteomics

Subject Areas: Biology and Bio-materials


Instruments: B21-High Throughput SAXS

Other Facilities: ESRF

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