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

人类几丁质酶样蛋白识别几丁质寡糖：在原子水平上破译 CodeChi 及其对细胞信号传导的影响

• 批准号: 525826480
• 负责人: Professor Dr. Jonathan Cramer
• 金额: --
• 依托单位: Institut für Pharmazeutische und Medizinische Chemie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/525826480?language=en
• 关键词: Chitin; oligosaccharide; recognition; human; chitinase

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.

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物。这些蛋白质的失调与炎症和感染性疾病以及癌症有关。几丁质酶样蛋白（Chitinase-like proteins，CLP）是一类重要的几丁质结合蛋白。然而，这些蛋白质的寡糖偏好，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没有完全理解。这一事实代表了开发基于几丁质的治疗剂和药物样几丁质衍生物的特别障碍。该项目旨在建立由CLP识别几丁质和CLP相关疾病相关过程的调制之间的联系。选择CLP YKL-40（CHI 3L 1）作为代表性模型系统。这种蛋白质是CLP家族的治疗相关成员，其与几种炎性疾病和癌症的病理学有关。在本项目的范围内，YKL-40对不同取代的甲壳素寡糖（COS）的特异性将在原子水平上采用计算和实验方法的多学科方法进行阐明。随后，将分析所观察到的配体偏好与相应蛋白质亚位点的结构之间的联系。然后，该数据将作为导出定量和预测性结构-亲和力模型的基础。此外，将仔细检查COS对YKL-40效应子功能的调节。这将包括分析COS结合后蛋白质的结构和动力学性质的变化。此外，将采用适当的生物物理学工具在分子水平上检查YKL-40与其主要受体IL-13 R α2之间的相互作用。这些实验将通过使用合适的报告细胞系的细胞测定来支持，以研究YKL-40在细胞水平上识别COS的功能后果。预期的结果将使人类先天免疫系统的甲壳素识别深入的机制洞察。从这项研究中得出的结论将作出有价值的贡献，开发新的药物靶向人类CLPs的治疗目的。