Chitin oligosaccharide recognition by human chitinase-like proteins: Deciphering CodeChi at the atomistic level and its impact on cellular signaling

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Chitin and chitosan polymers are recognized as markers of infection by the human immune system. Dysregulation of these proteins has been linked to inflammatory- and infectious diseases, as well as cancer. Chitinase-like proteins (CLPs) are an important class of chitin-binding proteins in humans. However, the oligosaccharide preferences of these proteins, particularly regarding the exact chemical ligand composition (i.e., CodeChi parameters), as well as the functional consequences of chitin recognition are incompletely understood. This fact represents a particular hurdle for the development of chitin-based therapeutics and drug-like chitin derivatives. This project aims to establish a connection between chitin recognition by CLPs and the modulation of CLP-associated disease-relevant processes. The CLP YKL-40 (CHI3L1) is chosen as a representative model system. This protein is a therapeutically relevant member of the CLP family that has been implicated in the pathology of several inflammatory diseases and cancers. Within the scope of this project, the specificity of YKL-40 against differentially substituted chitin oligosaccharides (COS) will be elucidated on an atomistic level in a multi-disciplinary approach applying computational and experimental methods. Subsequently, the link between the observed ligand preferences and the structure of the respective protein sub-sites will be analyzed. This data will then serve as the basis for deriving a quantitative and predictive structure–affinity model. Furthermore, the modulation of YKL-40 effector functions by COS will be scrutinized. This will encompass an analysis of the change in structural and dynamic properties of the protein upon COS binding. In addition, the interaction between YKL-40 and its main receptor, IL-13Rα2, will be examined on a molecular level by employing suitable biophysical tools. These experiments will be supported with cellular assays employing suitable reporter cell lines to investigate the functional consequences of COS recognition by YKL-40 on a cellular level. The expected results will enable a deep mechanistic insight into chitin recognition by the human innate immune system. The conclusions drawn from this study will make a valuable contribution to the development of novel drugs targeting human CLPs for therapeutic purposes.