Abstract
Chitin is an important structural component of numerous fungal pathogens and parasitic nematodes. The human macrophage chitotriosidase (HCHT) is a chitinase that hydrolyses glycosidic bonds between the N-acetyl-D-glucosamine units of this biopolymer. HCHT belongs to the Glycoside Hydrolase (GH) superfamily and contains a well-characterized catalytic domain appended to a chitin-binding domain (ChBDCHIT1). Although its precise biological function remains unclear, HCHT has been described to be involved in innate immunity. In this study, the molecular basis for interaction with insoluble chitin as well as with soluble chito-oligosaccharides has been determined. The results suggest a new mechanism as a common binding mode for many Carbohydrate Binding Modules (CBMs). Furthermore, using a phylogenetic approach, we have analysed the modularity of HCHT and investigated the evolutionary paths of its catalytic and chitin binding domains. The phylogenetic analyses indicate that the ChBDCHIT1 domain dictates the biological function of HCHT and not its appended catalytic domain. This observation may also be a general feature of GHs. Altogether, our data have led us to postulate and discuss that HCHT acts as an immune catalyser.
Highlights
Chitin is an important structural component of numerous fungal pathogens and parasitic nematodes
This modular protein is composed of a catalytic domain that belongs to family 18 of glycoside hydrolases (GH18) and of a carbohydrate-binding module, named ChBDCHIT1
Our data provide the molecular basis for chitin recognition by ChBDCHIT1 and, given the high conservation of the residues involved in chitin binding amongst Carbohydrate Binding Modules (CBMs) 14 as well as other CBM families, we postulated that this binding mode is a hallmark of CBM-carbohydrate interactions
Summary
Chitin is an important structural component of numerous fungal pathogens and parasitic nematodes. Defense proteins, including lectins, are known to play a crucial role in the initiation of innate immune mechanisms[4] These carbohydrate binding proteins include numerous members, which are notably synthetized by many organisms including plants and animals, thereby highlighting their ubiquity and necessity for survival[5]. The macrophage chitotriosidase (HCHT) is one of the three active chitinases synthetized by humans, together with acidic mammalian chitinase (AMCase) and the recently discovered exochitinase, chitobiase (CTBS)[9,10,11] This protein is synthetized as a 50-kDa soluble monomeric enzyme that is able to hydrolyse colloidal chitin. This modular protein is composed of a catalytic domain that belongs to family 18 of glycoside hydrolases (GH18) and of a carbohydrate-binding module, named ChBDCHIT1. Our data provide the molecular basis for chitin recognition by ChBDCHIT1 and, given the high conservation of the residues involved in chitin binding amongst CBMs 14 as well as other CBM families, we postulated that this binding mode is a hallmark of CBM-carbohydrate interactions
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