Inhibition of Mammalian Glycoprotein YKL-40

Abstract

YKL-40 is a mammalian glycoprotein associated with progression, severity, and prognosis of chronic inflammatory diseases and a multitude of cancers. Despite this well documented association, identification of the lectin's physiological ligand and, accordingly, biological function has proven experimentally difficult. YKL-40 has been shown to bind chito-oligosaccharides; however, the production of chitin by the human body has not yet been documented. Possible alternative ligands include proteoglycans, polysaccharides, and fibers like collagen, all of which makeup the extracellular matrix. It is likely that YKL-40 is interacting with these alternative polysaccharides or proteins within the body, extending its function to cell biological roles such as mediating cellular receptors and cell adhesion and migration. Here, we consider the feasibility of polysaccharides, including cello-oligosaccharides, hyaluronan, heparan sulfate, heparin, and chondroitin sulfate, and collagen-like peptides as physiological ligands for YKL-40. We use molecular dynamics simulations to resolve the molecular level recognition mechanisms and calculate the free energy of binding the hypothesized ligands to YKL-40, addressing thermodynamic preference relative to chito-oligosaccharides. Our results suggest that chitohexaose and hyaluronan preferentially bind to YKL-40 over collagen, and hyaluronan is likely the preferred physiological ligand, because the negatively charged hyaluronan shows enhanced affinity for YKL-40 over neutral chitohexaose. Collagen binds in two locations at the YKL-40 surface, potentially related to a role in fibrillar formation. Finally, heparin non-specifically binds at the YKL-40 surface, as predicted from structural studies. Overall, YKL-40 likely binds many natural ligands , but its concurrence with physical maladies may be related to associated increases in hyaluronan.

Chitinase 3-like 1-CD44 interaction promotes metastasis and epithelial-to-mesenchymal transition through β-catenin/Erk/Akt signaling in gastric cancer

“…To gain insight into the molecular mechanistic basis of the tumor facilitative effect of CHI3L1 in GC, we sought to identify CHI3L1 interacting partners. Here, we speculated that CD44 may constitute a potential receptor for CHI3L1 as they have respectively been shown to bind hyaluronic acid (HA, as its receptor) [ 27 ] and hyaluronan (as the likely preferred physiological ligand) [ 28 ]. First, we examined the expression level of CHI3L1, CD44, and IL-13Rα2 in a panel of human GC cells (Fig.…”

“…As hyaluronan constitutes the likely preferred physiological ligand of CHI3L1 [28] and CD44 functions as a hyaluronan receptor, we speculated that CD44 may thus be a potential CHI3L1 receptor as well. In the present study, by using co-IP and co-location assay in two GC cell lines, we confirmed that CHI3L1 binds to CD44.…”

“…Many lines of evidence indicated the tight relationship between CHI3L1 and HA, which together were considered as noninvasive markers of liver fibrosis [ 40 – 43 ]. As hyaluronan constitutes the likely preferred physiological ligand of CHI3L1 [ 28 ] and CD44 functions as a hyaluronan receptor, we speculated that CD44 may thus be a potential CHI3L1 receptor as well. In the present study, by using co-IP and co-location assay in two GC cell lines, we confirmed that CHI3L1 binds to CD44.…”

Ym1 induces RELMα and rescues IL-4Rα deficiency in lung repair during nematode infection

“…Whilst we have not directly explored whether Ym1 influences collagen biosynthesis or degradation, our data suggests Ym1 may regulate collagen fibril formation by controlling the quantity of epithelia-derived RELMα. Interestingly YKL-40, a CLP expressed in humans that has strong functional similarities to murine Ym1, not only contains binding motifs for heparin and hyaluronan [57], major constituents of the extracellular matrix, but also for type I collagen [58]. Moreover, binding of YKL-40 to collagen was shown to alter collagen structure or behaviour in a way that prevented cleavage of fibrils and hence aided collagen stability [58,59].…”

Chitinases and chitinase-like proteins as biomarkers in neurologic disorders

“…CLPs exhibit lectin properties and can bind to extracellular matrix components such as hyaluronan or proteoglycans and cell surface glycosaminoglycans. 26 The physiologic functions of CLPs are not entirely understood, but they appear to be involved in a plethora of biological processes, including tissue remodeling, inflammation, and regulation of the immune response. CHI3L1 or YKL-40 is by far the most described CLP because of its implication in diverse pathologic conditions.…”