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

甲壳素和壳聚糖聚合物被认为是人类免疫系统感染的标志。这些蛋白质的失调与炎症性和感染性疾病以及癌症有关。几丁质酶样蛋白(CLPs)是人类体内一类重要的几丁质结合蛋白。然而，这些蛋白质的低聚糖偏好，特别是关于确切的化学配体组成(即Codechi参数)，以及甲壳素识别的功能后果还不完全清楚。这一事实对以甲壳素为基础的疗法和类药物甲壳素衍生物的发展来说是一个特别的障碍。该项目旨在建立CLP对甲壳素的识别和CLP相关疾病相关过程的调节之间的联系。选择中电YKL-40(CHI3L1)作为典型系统。这种蛋白是CLP家族中一个具有治疗意义的成员，与几种炎症性疾病和癌症的病理有关。在这个项目的范围内，YKL-40对差异取代的甲壳素低聚糖(COS)的特异性将在原子水平上通过应用计算和实验方法在多学科方法中阐明。随后，将分析观察到的配基偏好与相应蛋白质亚基结构之间的联系。然后，这些数据将作为推导出定量和预测性结构亲和力模型的基础。此外，还将仔细研究COS对YKL-40效应器功能的调节。这将包括分析COS结合时蛋白质的结构和动态性质的变化。此外，YKL-40与其主要受体IL-13Rα2之间的相互作用将通过适当的生物物理工具在分子水平上进行研究。这些实验将通过使用合适的报告细胞系的细胞分析来支持，以在细胞水平上研究YKL-40识别COS的功能后果。预期的结果将使人们能够从机制上深入了解人类先天免疫系统对甲壳素的识别。本研究得出的结论将为开发针对人CLP的治疗新药做出有价值的贡献。

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.