PADI4-Cit - Precision bifunctional peptide tools to understand protein citrullination

PADI4-Cit - 用于了解蛋白质瓜氨酸化的精密双功能肽工具

• 批准号: EP/Y029704/1
• 负责人: Huawu Yin
• 金额: $ 25.55万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY029704%2F1
• 关键词: PADI4; Cit; Precision; bifunctional; peptide

Protein citrullination is a posttranslational modification (PTM) involved in a wide range of biological functions including epigeneticgene regulation and the innate immune response. Its dysregulation is implicated in the progress of diverse pathogeneses. Despitethese important roles, our understanding of citrullination remains in its infancy. Citrullination in mammals is catalysed by fivepromiscuous isozymes from the peptidylarginine deiminase (PADI) family, which display overlapping substrate specificities and arange of tissue expression patterns. This complex landscape makes precise understanding of the effects of citrullination challenging,with no general strategies currently available to explore citrullination at the single substrate level. To dissect this complicated system,I aim to develop bifunctional chemical tools to recruit PADI enzymes to specific substrates and genes, allowing investigation of theeffects of citrullination on protein function and gene expression with a level of precision and specificity not currently possible. I willfocus on PADI4, the primarily nuclear member of the PADIs, producing methods to precisely understand the biochemical effects ofsingle citrullination events in a cell-based context at the substrate level. My new bifunctional tools will be used to address two relatedgoals: understanding the effect of citrullination on 1) individual protein substrates, and 2) gene regulation. Results from this workshould shed light on this relatively poorly understood PTM, providing new insight into the effects of citrullination on protein functionand a blueprint for future applications to study other substrates and PADIs, with the potential to provide new avenues for therapeuticintervention.

蛋白瓜氨酸化是一种翻译后修饰（PTM），涉及广泛的生物学功能，包括表观遗传基因调控和先天免疫反应。它的失调与多种发病机制的进展有关。尽管有这些重要的作用，我们对瓜氨酸化的理解仍处于起步阶段。哺乳动物的瓜氨酸化是由来自肽精氨酸脱亚胺酶（PADI）家族的五种混杂同工酶催化的，它们表现出重叠的底物特异性和组织表达模式的多样性。这种复杂的情况使得精确理解瓜氨酸化的影响具有挑战性，目前还没有一般的策略可以在单一底物水平上探索瓜氨酸化。为了解剖这个复杂的系统，我的目标是开发双功能化学工具，将PADI酶招募到特定的底物和基因上，从而以目前不可能的精度和特异性水平研究瓜氨酸化对蛋白质功能和基因表达的影响。我将重点关注padi的主要核成员PADI4，并在底物水平上精确理解基于细胞的背景下单个瓜氨酸化事件的生化效应。我的新双功能工具将用于解决两个相关的目标：了解瓜氨酸化对1)单个蛋白质底物的影响，以及2)基因调控。这项工作的结果将阐明这一相对不为人所知的PTM，为瓜氨酸化对蛋白质功能的影响提供新的见解，并为未来研究其他底物和padi提供蓝图，并有可能为治疗干预提供新的途径。