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

What is it about?

Remodelling of the cellular microenvironment, consisting in extracellular matrix, is a major regulator of organ development and of pathologies such as tumour growth and fibrosis. This remodelling is achieved by a variety of enzymes, including cross-linking enzymes of the lysyl oxidase family. We have limited knowledge of the structure and of the substrate specificity of these secreted enzymes. Lysyl oxidases share a conserved catalytic domain responsible for the cross-linking activity, but differ in the rest of the protein : LOXL2 contains four repeats of scavenger receptor cysteine-rich (SRCR) domains of unknown function. We thus investigated by X-ray scattering and electron microscopy the low-resolution structure of LOXL2. 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 also detected direct interaction between LOXL2 and tropoelastin, as well as LOXL2 activity on tropoelastin. Using proteomics, we identified several reaction products, named allysines, in tropoelastin. We also detected cross-linked peptides of tropoelastin. The elastin-like material generated by LOXL2-mediated cross-linking was resistant to proteolysis and displayed mechanical properties similar to mature elastin. Finally, we detected the co-distribution of LOXL2 and elastin in the vascular wall. Altogether, these data identify a new activity for LOXL2 as it could participate in elastogenesis in the cardiovascular system and in skin. Our data also suggest that LOXL2 could be used as a means of cross-linking tropoelastin in vitro for biomimetic and cell compatible tissue engineering purposes.

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