Mechanism of binding of mycobacterial glycolipids to mincle, a stimulatory glycan-binding receptor on macrophages

分枝杆菌糖脂与巨噬细胞上的刺激性聚糖结合受体 mincle 的结合机制

• 批准号: BB/K007718/1
• 负责人: Kurt Drickamer
• 金额: $ 51.98万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK007718%2F1
• 关键词: Mechanism; binding; mycobacterial; glycolipids; mincle

Different cells are characterised by different patterns of sugars linked to their surfaces. One mechanism used by the innate immune system, which responds directly to microbial pathogens before a specific antibody response is mounted, is to identify pathogens based on the way the sugars on their surfaces differ from those of the host. The work we propose is directed toward developing a molecular understanding of how mincle, a sugar-binding receptor on the surface of macrophages from humans and other mammals, binds to unusual sugars on the surface of mycobacteria, which are the causative agent of tuberculosis in humans, cows and other mammals. Mincle is believed to play a role in the complex interaction between mycobacteria and the host immune system that leads to development of tuberculosis.The approaches that will be undertaken include creating small molecules that mimic portions of the cell surface of the mycobacteria to see which features are essential for binding to mincle and leading to stimulation of macrophages. The molecules will also facilitate structural analysis of how the binding occurs. Mincle from humans, cows and mice will be examined. The first two species are important because of the way that naturally occurring mycobacterial infections affect them, leading to an enormous worldwide disease burden in humans and providing a major challenge to the safety of the domestic cattle industry. Mice are used as models for study of mincle function in the whole organism, so it is important to demonstrate that mincle from mice has the same properties as the human and cow proteins. In addition to these studies of the binding of mincle to mycobacterial sugars, further studies will address the question of how mincle interacts with other proteins in the macrophage membrane so that the binding of sugar targets can be translated into stimulation of the macrophages.This is a basic science proposal directed toward elucidating the mechanisms underlying the functions of a poorly understood receptor. However, there are clear practical goals that will benefit from the information that will be obtained, including the fact that an improved understanding of how mycobacteria can interact with the host immune system may provide insights into how this process can be altered in a way that reduces the disease burden. Most directly, this understanding will provide knowledge necessary to exploit the fact that mycobacterial surface components are able to stimulate the immune system and improve production of antibodies. Up to now, this property has not been used in human vaccine development because of the complexity and uncontrolled nature of the reaction to mycobacteria, but the proposed studies will help to define simpler molecules that can trigger the beneficial effects in more controlled ways for vaccine development in humans and animals.

不同的细胞的特征在于连接到其表面的糖的不同模式。先天免疫系统使用的一种机制是在特异性抗体反应之前直接对微生物病原体作出反应，该机制是根据病原体表面上的糖与宿主表面糖的不同方式来识别病原体。我们提出的工作是针对开发一种分子理解，即人类和其他哺乳动物巨噬细胞表面的糖结合受体mincle如何与分枝杆菌表面的不寻常糖结合，分枝杆菌是人类，奶牛和其他哺乳动物结核病的病原体。Mincle被认为在分枝杆菌和宿主免疫系统之间复杂的相互作用中发挥作用，导致结核病的发展。将采取的方法包括创造模拟分枝杆菌细胞表面部分的小分子，以观察哪些特征对于与Mincle结合并导致刺激巨噬细胞至关重要。这些分子还将促进结合如何发生的结构分析。将检查人、牛和小鼠的碎肉。前两个物种很重要，因为自然发生的分枝杆菌感染影响它们的方式，导致人类巨大的全球疾病负担，并对国内养牛业的安全提出了重大挑战。小鼠被用作研究整个生物体中碎肉功能的模型，因此证明来自小鼠的碎肉具有与人和牛蛋白相同的性质是重要的。除了这些研究mincle的结合分枝杆菌糖，进一步的研究将解决的问题，如何mincle与其他蛋白质在巨噬细胞膜，使糖的结合目标可以转化为刺激macrophages.This的基础科学的建议，旨在阐明机制的功能知之甚少的受体。然而，有明确的实际目标将受益于将获得的信息，包括以下事实：更好地了解分枝杆菌如何与宿主免疫系统相互作用，可以提供有关如何以减少疾病负担的方式改变这一过程的见解。最直接的是，这种理解将提供必要的知识，以利用分枝杆菌表面成分能够刺激免疫系统和提高抗体的产生。到目前为止，由于对分枝杆菌反应的复杂性和不受控制的性质，这种特性尚未用于人类疫苗开发，但拟议的研究将有助于定义更简单的分子，这些分子可以以更可控的方式触发人类和动物疫苗开发的有益效果。

项目成果

Mechanism of pathogen recognition by human dectin-2.

• DOI: 10.1074/jbc.m117.799080
• 发表时间: 2017-08-11
• 期刊: The Journal of biological chemistry
• 作者: Feinberg H;Jégouzo SAF;Rex MJ;Drickamer K;Weis WI;Taylor ME
• 通讯作者: Taylor ME

Binding Sites for Acylated Trehalose Analogs of Glycolipid Ligands on an Extended Carbohydrate Recognition Domain of the Macrophage Receptor Mincle.

在巨噬细胞受体Mincle的扩展碳水化合物识别结构域上的糖脂配体酰化的沙洛糖类似物的结合位点。

• DOI: 10.1074/jbc.m116.749515
• 发表时间: 2016-09-30
• 期刊: The Journal of biological chemistry
• 作者: Feinberg H;Rambaruth ND;Jégouzo SA;Jacobsen KM;Djurhuus R;Poulsen TB;Weis WI;Taylor ME;Drickamer K
• 通讯作者: Drickamer K

Convergent and divergent mechanisms of sugar recognition across kingdoms.

• DOI: 10.1016/j.sbi.2014.07.003
• 发表时间: 2014-10
• 期刊: CURRENT OPINION IN STRUCTURAL BIOLOGY
• 影响因子: 6.8
• 作者: Taylor, Maureen E.;Drickamer, Kurt
• 通讯作者: Drickamer, Kurt

Identification of serum glycoprotein ligands for the immunomodulatory receptor blood dendritic cell antigen 2.

• DOI: 10.1093/glycob/cwy050
• 发表时间: 2018-08-01
• 期刊: Glycobiology
• 影响因子: 4.3
• 作者: Kim JW;Budzak J;Liu Y;Jégouzo SAF;Drickamer K;Taylor ME
• 通讯作者: Taylor ME

Mouse mincle: characterization as a model for human mincle and evolutionary implications.

小鼠Mincle：表征是人类明确和进化意义的模型。

• DOI: 10.3390/molecules20046670
• 发表时间: 2015-04-15
• 期刊: Molecules (Basel, Switzerland)
• 作者: Rambaruth ND;Jégouzo SA;Marlor H;Taylor ME;Drickamer K
• 通讯作者: Drickamer K