Understanding the molecular basis of how the chemokine network is targeted by evasin proteins from tick saliva

了解蜱唾液中的 evasin 蛋白如何靶向趋化因子网络的分子基础

• 批准号: 2595602
• 金额: --
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2595602
• 关键词: Understanding; molecular; basis; how; chemokine

Chemokines are small, secreted proteins that are major drivers of inflammation, functioning via binding to GPCRs to recruit immune-inflammatory cells to damaged tissues. Ticks secrete small proteins called evasins, in saliva, that have the ability to bind and neutralise multiple chemokines, thus disabling the host chemokine network. This property allows ticks to feed for days without detection. Evasins have been shown to have potent anti-inflammatory effects in preclinical models, including in myocardial infarction and plaque inflammation. Over 40 tick evasins from multiple tick species have been identified to date, all with broad and promiscuous chemokine binding properties. We aim to study the properties of the interaction interfaces between evasins and chemokines using chemical and structural biology techniques. Protein fragments will be employed to understand the molecular basis of the multi-chemokine binding properties of evasins, and to investigate how evasins neutralise chemokine function. We also aim to understand more about the selectivity of these interactions through modification of fragments/proteins by chemical synthesis, expanding our rationale for chemical probe development. By mapping these protein-protein interactions using these chemical probes we hope to gain an understanding of how these interactions might be mimicked.

趋化因子是一种小型分泌蛋白，是炎症的主要驱动因素，通过与 GPCR 结合发挥作用，将免疫炎症细胞募集到受损组织。蜱虫在唾液中分泌一种叫做evasins的小蛋白质，它能够结合和中和多种趋化因子，从而使宿主趋化因子网络失效。这一特性使得蜱虫可以在不被发现的情况下进食数天。 Evasins 已被证明在临床前模型中具有有效的抗炎作用，包括心肌梗塞和斑块炎症。迄今为止，已从多个蜱种中鉴定出超过 40 种蜱逃逸素，它们都具有广泛且混杂的趋化因子结合特性。我们的目标是利用化学和结构生物学技术研究 evasin 和趋化因子之间相互作用界面的特性。蛋白质片段将用于了解 evasins 多趋化因子结合特性的分子基础，并研究 evasins 如何中和趋化因子功能。我们还旨在通过化学合成修饰片段/蛋白质来更多地了解这些相互作用的选择性，从而扩展我们化学探针开发的基本原理。通过使用这些化学探针绘制这些蛋白质-蛋白质相互作用，我们希望了解如何模拟这些相互作用。