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

TY - JOUR

T1 - Lysyl oxidase-like 2 (LOXL2)-mediated cross-linking of tropoelastin

AU - Schmelzer, Christian E H

AU - Heinz, Andrea

AU - Troilo, Helen

AU - Lockhart-Cairns, Michael P

AU - Jowitt, Thomas A

AU - Marchand, Marion F

AU - Bidault, Laurent

AU - Bignon, Marine

AU - Hedtke, Tobias

AU - Barret, Alain

AU - McConnell, James C

AU - Sherratt, Michael J

AU - Germain, Stéphane

AU - Hulmes, David J S

AU - Baldock, Clair

AU - Muller, Laurent

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

U2 - 10.1096/fj.201801860RR

DO - 10.1096/fj.201801860RR

M3 - Journal article

C2 - 30676771

SN - 0892-6638

VL - 33

SP - 5468

EP - 5481

JO - F A S E B Journal

JF - F A S E B Journal

IS - 4

ER -