Lysine Oxidation by LOXL2 in Single Strands Versus Triple Helices: Implications for Collagen‐Related Diseases

Abstract

ABSTRACT Collagen cross‐linking is essential for the structural integrity of the extracellular matrix. In several pathological conditions, the triple‐helical core of collagen is disrupted, and proline‐rich single strands occur. Lysyl oxidases (LOXs), enzymes that initiate cross‐linking by catalyzing the oxidative deamination of lysine to allysine residues, are upregulated in disease. Surprisingly little is known about the selectivity of LOXs. LOX‐initiated cross‐linking is believed to occur exclusively in the unstructured terminal domains of collagen, the telopeptides. But is this really the case? Herein, we show, with a combination of tailored chemical probes, enzymatic assays, CD and NMR spectroscopic analyses, that LOXL2 oxidizes Lys in proline‐rich single strands but not in triple helices. A comparison of Lys‐containing collagen model peptides (CMPs) with Lys‐containing telopeptides revealed comparable or higher oxidation rates in proline‐rich segments. The data suggest that LOXL2‐initiated cross‐linking occurs in pathologically disrupted triple‐helical domains, offering insights into aberrant extracellular matrix stiffening.