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 in vivo, but its concurrence with physical maladies may be related to associated increases in hyaluronan.
Document Type
Article
Publication Date
1-4-2017
Digital Object Identifier (DOI)
https://doi.org/10.1074/jbc.M116.764985
Funding Information
This work was supported by Kentucky Science and Engineering Foundation Grant KSEF-148-502-13-307). Computational time for this research was provided by the Extreme Science and Engineering Discovery Environment (83), which is supported by National Science Foundation Grant ACI-1053575 under Allocation MCB090159.
Related Content
This article contains supplemental text, Tables S1–S6, Figs. S1–S8, and Movies S1–S3.
Repository Citation
Kognole, Abhishek A. and Payne, Christina M., "Inhibition of Mammalian Glycoprotein YKL-40 IDENTIFICATION OF THE PHYSIOLOGICAL LIGAND" (2017). Chemical and Materials Engineering Faculty Publications. 42.
https://uknowledge.uky.edu/cme_facpub/42
Supplemental Data
jbc.M116.764985-2.mov (5700 kB)
Supplemental Movie S1
jbc.M116.764985-3.mov (3671 kB)
Supplemental Movie S2
jbc.M116.764985-4.mov (7767 kB)
Supplemental Movie S3
Included in
Amino Acids, Peptides, and Proteins Commons, Biochemistry, Biophysics, and Structural Biology Commons, Chemical Engineering Commons, Genetics and Genomics Commons, Materials Science and Engineering Commons
Notes/Citation Information
Published in The Journal of Biological Chemistry, v. 292, no. 7, p. 2624-2636.
This research was originally published in The Journal of Biological Chemistry. Abishek A. Kognole and Christina M. Payne. Inhibition of Mammalian Glycoprotein YKL-40 IDENTIFICATION OF THE PHYSIOLOGICAL LIGAND. J. Biol. Chem. 2017; 292:2624-2636. © 2017 by The American Society for Biochemistry and Molecular Biology. Inc.
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