Elucidating the molecular, structural and supramolecular basis of 33-mer gliadin oligomers and their role in gluten-related disorders

阐明 33 聚体麦醇溶蛋白寡聚物的分子、结构和超分子基础及其在麸质相关疾病中的作用

• 批准号: 430578458
• 负责人: Dr. Veronica Isabel Dodero Bendana
• 金额: --
• 依托单位: Arbeitskreis Organische Chemie III
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/430578458?language=en
• 关键词: Elucidating; molecular; structural; supramolecular; basis

The 33-mer gliadin peptide is a key player in the context of gluten-related disorders, a group of immunological disorders with a high prevalence in Western societies (1-7%). This 33-mer amino acid is the product of the incomplete proteolysis of gliadins present in wheat gluten and it possesses the gluten-immunodominant sequence that triggers autoimmunity in susceptible individuals. Nevertheless, the molecular events triggering gluten-related disorders have not been described yet. We showed that the α-gliadin mixtures and the 33-mer gliadin peptide are able to form soluble oligomers and superstructures under physiological conditions. Importantly, we discovered that the 33-mer peptide suffers a structural transition towards a parallel β-sheet structure during the self-assembly process. Oligomerisation and a parallel beta-sheet structure formation are the hallmarks of amyloidosis. Moreover, we demonstrated that the 33-mer superstructures activate the innate immune response in macrophages mediated by Toll-like Receptors (TLRs). In this sense, our working hypothesis is that the accumulation and aggregation of the 33-mer peptide could be an unknown and key factor which triggers the disease. Therefore, the aim of this project is to elucidate the molecular, structural and supramolecular basis of 33-mer oligomerization and the behaviour of the 33-mer nanostructures in their interaction and transport in gut epithelial cell models. This multidisciplinary project combines different methodologies including peptide chemistry, structural and supramolecular characterisation, cellular biology approaches, proteomics and super-resolution optical microscopy. The combination of these methodologies is the win-win strategy to quantify and understand the role of the 33-mer oligomers and superstructures as triggers of the disease. Our findings will open new avenues in the understanding of gluten-related disorders directed towards the design of new effective treatments beyond the gluten-free diet.

33-mer麦醇溶蛋白肽是谷蛋白相关疾病背景下的关键参与者，谷蛋白相关疾病是一组在西方社会中具有高患病率（1-7%）的免疫性疾病。这种33聚体氨基酸是小麦面筋中存在的麦醇溶蛋白的不完全蛋白水解的产物，并且它具有在易感个体中触发自身免疫的面筋免疫显性序列。然而，触发谷蛋白相关疾病的分子事件尚未被描述。我们发现，α-麦醇溶蛋白混合物和33-mer麦醇溶蛋白肽能够在生理条件下形成可溶性寡聚体和超结构。重要的是，我们发现33-mer肽在自组装过程中经历了向平行β-折叠结构的结构转变。寡聚化和平行β折叠结构形成是淀粉样变性的标志。此外，我们证明了33-mer超结构激活巨噬细胞中由Toll样受体（TLR）介导的先天免疫应答。从这个意义上说，我们的工作假设是，33-mer肽的积累和聚集可能是引发疾病的未知和关键因素。因此，该项目的目的是阐明33-mer寡聚化的分子，结构和超分子基础以及33-mer纳米结构在肠道上皮细胞模型中相互作用和运输的行为。这个多学科项目结合了不同的方法，包括肽化学，结构和超分子表征，细胞生物学方法，蛋白质组学和超分辨率光学显微镜。这些方法的组合是量化和理解33-mer寡聚体和超结构作为疾病触发因素的作用的双赢策略。我们的研究结果将为理解麸质相关疾病开辟新的途径，旨在设计新的有效治疗方法，而不仅仅是无麸质饮食。