title: Human YKL-39 is a pseudo-chitinase with retained chitooligosaccharide-binding properties.
abstract: The chitinase-like proteins YKL-39 (chitinase 3-like-2) and YKL-40 (chitinase 3-like-1) are highly expressed in a number of human cells independent of their origin (mesenchymal, epithelial or haemapoietic). Elevated serum levels of YKL-40 have been associated with a negative outcome in a number of diseases ranging from cancer to inflammation and asthma. YKL-39 expression has been associated with osteoarthritis. However, despite the reported association with disease, the physiological or pathological role of these proteins is still very poorly understood. Although YKL-39 is homologous to the two family 18 chitinases in the human genome, it has been reported to lack any chitinase activity. In the present study, we show that human YKL-39 possesses a chitinase-like fold, but lacks key active-site residues required for catalysis. A glycan screen identified oligomers of N-acetylglucosamine as preferred binding partners. YKL-39 binds chitooligosaccharides and a newly synthesized derivative of the bisdionin chitinase-inhibitor class with micromolar affinity, through a number of conserved tryptophan residues. Strikingly, the chitinase activity of YKL-39 was recovered by reverting two non-conservative substitutions in the active site to those found in the active enzymes, suggesting that YKL-39 is a pseudo-chitinase with retention of chitinase-like ligand-binding properties.
authors: Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK.
authors: Marianne
authors: M
authors: Schimpl
authors: Christina L
authors: CL
authors: Rush
authors: Marie
authors: M
authors: Betou
authors: Ian M
authors: IM
authors: Eggleston
authors: Anneliese D
authors: AD
authors: Recklies
authors: Daan M F
authors: DM
authors: van Aalten
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism; D054392:Adipokines / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D020134:Catalytic Domain; D002686:Chitin / Q000378:metabolism; D000071451:Chitinase-3-Like Protein 1; D002688:Chitinases / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D037102:Lectins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009844:Oligosaccharides / Q000737:chemistry / Q000378:metabolism; D017354:Point Mutation; D011487:Protein Conformation; D017510:Protein Folding; D014364:Tryptophan / Q000378:metabolism
chemical_list: D054392:Adipokines; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D004791:Enzyme Inhibitors; D037102:Lectins; D009844:Oligosaccharides; D002686:Chitin; D014364:Tryptophan; D002688:Chitinases; D000117:Acetylglucosamine