Glycosaminoglycan Recognition by YKL-40: Potential Regulation in Disease

YKL-40 (CHI3L1) is a secreted chitinase-like protein involved in inflammation, tissue remodeling, angiogenesis, and cancer. Although its biological activities have been extensively investigated, the molecular mechanisms regulating its extracellular interactions remain incompletely understood. YKL-40 binds several glycosaminoglycans (GAGs), including heparin (hep), heparan sulfate (HS), dermatan sulfate (DS), and hyaluronan (HA). YKL-40-GAG interactions are influenced by the GAG chain length, sulfation, and uronic acid composition, suggesting that YKL-40 selectively recognizes specific structural features of GAG chains rather than electrostatic interactions alone. YKL-40 is known to interact with the HS-containing cell-surface receptors CD44v3, syndecan-1, and syndecan-4, which have been implicated in YKL-40-mediated signaling associated with tumor progression and angiogenesis. Because HS structures are dynamically regulated through sulfation and the C5-epimerization of D-glucuronic acid (GlcA) to L-iduronic acid (IdoA), pathological remodeling may alter the binding properties of HS chains of these receptors. This hypothesis-driven review examines the structural determinants of YKL-40-GAG recognition and proposes a mechanism by which disease-associated changes in HS sulfation, the uronic acid composition, and motif organization could alter YKL-40 binding affinity for HS-containing receptors, potentially influencing their downstream signaling. However, whether such remodeling directly alters YKL-40 binding or signaling remains to be experimentally established. Understanding how receptor-associated HS structures influence YKL-40 recognition may provide new insights into its context-dependent biological activity and potential therapeutic targeting.