Alex Meier (University of Kansas, University of Kansas)| HeeJung Moon (University of Kansas)| Victor Day (University of Kansas)| Minae Mure (University of Kansas)
Lysyl oxidase-like 2 (LOXL2) is associated with tumor metastasis/invasion and organ fibrosis via promoting the extracellular matrix (ECM) stiffening. LOXL2 is a Cu2+ and lysine tyrosylquinone (LTQ) dependent amine oxidase and known to catalyze the oxidative deamination of peptidyl lysine and hydroxyl lysine residues in ECM proteins (e.g. collagens and elastin). The LTQ cofactor of LOXL2 is posttranslationaly derived from peptidyl Lys and Tyr residues. Recently, an X-ray structure of a Zn2+-bound precursor of LOXL2 became available. Surprisingly, the precursor residues of the LTQ cofactor, Lys653 and Tyr689 were 16.6 Å apart, indicating that substantial conformational change is required for the biogenesis of the LTQ cofactor. A 3D homology modeling study of the catalytic domain of lysyl oxidase (LOX) based on the precursor structure of LOXL2 even suggested a possibility of disulfide bond shuffling during biogenesis. In this study, we focus on a catalytically-competent LOXL2 and aim to gain insight into the active site environment. Comparative UV-vis spectroscopic studies of LOXL2 inhibited with 2-hydrazinopyridine (2-HP) and model compound mimicking LTQ-2HP were conducted. We obtained a strong evidence to support that the LTQ cofactor resides within 2.8 Å from the active site Cu2+ and a large conformational change is not required for the formation of the LTQ cofactor.