Structural Plasticity in Antigen Selection

抗原选择中的结构可塑性

• 批准号: BB/L010402/1
• 负责人: Joern Werner
• 金额: $ 80.91万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL010402%2F1
• 关键词: Structural; Plasticity; Antigen; Selection

Our bodies have evolved an intricate and powerful system to distinguish "self" from "non-self" called the immune system. This formidable task force allows us fight off foreign invaders such as viruses and bacterial pathogens. Since it can cause devastation and disease when it is going wrong, e.g. by attacking the self, such as in auto immune diseases, it needs to be highly regulated and finely tuned. The proposed research investigates a key process to regulate to power of the immune system. Almost every cell in an individual constantly presents samples of short protein fragments from the inside of the cell to the immune system. If these samples are recognised as foreign, the cell will be destroyed. Hence, the control over which peptide samples are shown to the immune system constitutes a key control mechanism to direct the immune response. We are investigating the molecular mechanism of how these representative samples are selected at the cellular level and at the molecular level. We propose that the ability of the protein, called MHC, that recognises the peptides to be malleable and change shape is essential to perform the selection task. We hope that by understanding the molecular nature of this recognition process and its relationship to directing the immune response we will in the future develop new ways of fighting diseases such as cancer and auto-immune diseases by directing an individual's capacity to eradicate what it perceives as non-self.

我们的身体进化出了一个复杂而强大的系统，用来区分“自我”和“非我”，称为免疫系统。这支强大的特遣部队使我们能够击退外来入侵者，如病毒和细菌病原体。由于它会在出错时造成破坏和疾病，例如通过攻击自我，例如在自身免疫性疾病中，它需要高度监管和微调。这项拟议的研究调查了调节免疫系统能力的一个关键过程。个体中的几乎每个细胞都不断地将短蛋白质片段的样本从细胞内部呈现给免疫系统。如果这些样本被认为是外来的，细胞将被销毁。因此，对免疫系统显示哪些多肽样本的控制构成了指导免疫反应的关键控制机制。我们正在研究如何在细胞水平和分子水平上选择这些具有代表性的样本的分子机制。我们认为，这种名为MHC的蛋白质识别多肽具有可塑性并改变形状的能力对于执行选择任务是必不可少的。我们希望，通过了解这种识别过程的分子本质及其与指导免疫反应的关系，我们将在未来开发抗击癌症和自身免疫性疾病等疾病的新方法，通过指导个人消除其所认为的非我的能力。

项目成果

Kinetics of Abacavir-Induced Remodelling of the Major Histocompatibility Complex Class I Peptide Repertoire.

• DOI: 10.3389/fimmu.2021.672737
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Illing PT;van Hateren A;Darley R;Croft NP;Mifsud NA;King S;Kostenko L;Bharadwaj M;McCluskey J;Elliott T;Purcell AW
• 通讯作者: Purcell AW

Selector function of MHC I molecules is determined by protein plasticity.

• DOI: 10.1038/srep14928
• 发表时间: 2015-10-20
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Bailey A;Dalchau N;Carter R;Emmott S;Phillips A;Werner JM;Elliott T
• 通讯作者: Elliott T

Plasticity of empty major histocompatibility complex class I molecules determines peptide-selector function.

• DOI: 10.1016/j.molimm.2015.03.010
• 发表时间: 2015-12
• 期刊: Molecular immunology
• 影响因子: 3.6
• 作者: van Hateren A;Bailey A;Werner JM;Elliott T
• 通讯作者: Elliott T

The partial dissociation of MHC class I-bound peptides exposes their N terminus to trimming by endoplasmic reticulum aminopeptidase 1.

• DOI: 10.1074/jbc.ra117.000313
• 发表时间: 2018-05-18
• 期刊: The Journal of biological chemistry
• 作者: Papakyriakou A;Reeves E;Beton M;Mikolajek H;Douglas L;Cooper G;Elliott T;Werner JM;James E
• 通讯作者: James E

Direct evidence for conformational dynamics in major histocompatibility complex class I molecules.

• DOI: 10.1074/jbc.m117.809624
• 发表时间: 2017-12-08
• 期刊: The Journal of biological chemistry
• 作者: van Hateren A;Anderson M;Bailey A;Werner JM;Skipp P;Elliott T
• 通讯作者: Elliott T