Characterization of YKL-40 Binding to Extracellular Matrix Glycosaminoglycans.

YKL-40 is a chitinase-like glycoprotein implicated in various pathological processes, yet its glycosaminoglycan (GAG) binding profile beyond heparin has not been examined. In this study, we performed a Microscale Thermophoresis (MST) analysis on the heparin-binding glycoprotein YKL-40 using low molecular weight GAG oligosaccharides. We identified two new GAG ligands, dermatan sulfate (DS) and hyaluronan (HA), while chondroitin sulfate (CS) showed no detectable binding affinity. The results show that heparin is bound with the strongest affinity, followed by DS and HA. To further investigate these differences, molecular docking was used to evaluate possible binding modes. Molecular docking results indicated that both heparin and DS interacted with the same site on YKL-40, the heparin-binding site at residues 143-149, suggesting a multifunctional binding region that may act as a competitive switch or integration hub for spatially regulated signaling. Together, these findings expand the known ligand profile of YKL-40 and offer new insights into its ECM-context-dependent roles, with implications for targeting YKL-40 in diseases involving chronic inflammation, fibrosis, and cancer progression.