Structural analysis of Netrin 1 signal initiation and transduction

Netrin 1 信号起始和转导的结构分析

• 批准号: MR/L017776/1
• 负责人: Christian Siebold
• 金额: $ 79.71万
• 依托单位: University of Oxford
• 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=MR%2FL017776%2F1
• 关键词: Structural; analysis; Netrin; signal; initiation

During the development of multicellular organisms (e.g. humans), cell-to-cell communication is vital. Trillions of growing cells need to end up in the right place in order to fulfil their destiny. Even in a full grown body, our cells and tissues still need to communicate, and new cells grow and migrate to repair and renew our tissues. To achieve this crucial job, the body uses signalling molecules and receptors to direct and guide cells, and to allow communication between different cells in the body. These molecules signal like traffic lights, stopping or allowing growth and cell movement.The netrins (in particular NET-1) are a family of signalling molecules with multiple functions in human biology. They have been initially identified as crucial signals responsible for guiding axons in the developing nervous system, for which they were named after the Sanskrit word "netr", which means "one who guides". New research has also associated netrins to the development and maintenance of non-neural tissue, such as the vascular and muscle systems as well as mammary gland and the heart. The importance of netrins signalling in human disease has become increasingly clear as mutations in netrins and their receptors have been linked to Parkinson's disease and amyotrophic lateral sclerosis (ALS), suggesting that netrin-mediated changes in synapse function may influence human neurodegenerative diseases. Moreover, it has been shown that netrins are activated and serving as pro-cancer factors in various human cancers, such as pancreatic adenocarcinomas, metastatic breast cancer, non-small-cell lung cancer and neuroblastoma. Specific disruption of netrin binding to its receptors could therefore represent an efficient anti-cancer strategy.Genetic studies have provided a broad brush-stroke understanding of these mechanisms, however much still remains to be found out about impaired netrin signalling leading to human disease. Crucially, the details (fine brush-stroke) of netrin recognition at the surface of cells and how information is transmitted into the cell are only poorly understood. This level of detail can greatly aid drug design. We aim to unravel these fundamental mechanisms by providing molecular snapshots of netrin-receptor complexes using the methods of X-ray crystallography combined with functional, biophysical and cell-based experiments. Our results will be placed in a context of neuronal systems and whole organisms via collaborations with neurobiologists to get an integrated picture and a deeper understanding. This will potentially allow the structure-guided design of new therapeutic and/or diagnostic approaches.

在多细胞生物（如人类）的发育过程中，细胞间的通讯至关重要。数以万亿计的细胞需要在正确的地方生长，以完成它们的命运。即使在一个完整的身体中，我们的细胞和组织仍然需要交流，新细胞生长和迁移以修复和更新我们的组织。为了实现这一关键工作，身体使用信号分子和受体来指导和引导细胞，并允许体内不同细胞之间的通信。这些分子像交通信号灯一样发出信号，停止或允许生长和细胞运动。netrins（特别是NET-1）是一个在人类生物学中具有多种功能的信号分子家族。它们最初被确定为负责指导神经系统发育中轴突的关键信号，因此它们以梵文单词“netr”命名，意思是“指导者”。新的研究还将netrins与非神经组织的发育和维持联系起来，如血管和肌肉系统以及乳腺和心脏。netrin信号在人类疾病中的重要性已经变得越来越清楚，因为netrin及其受体的突变与帕金森病和肌萎缩侧索硬化症（ALS）有关，这表明netrin介导的突触功能变化可能影响人类神经退行性疾病。此外，已经显示netrin被激活并在各种人类癌症中充当促癌因子，例如胰腺癌、转移性乳腺癌、非小细胞肺癌和神经母细胞瘤。因此，特异性破坏netrin与其受体的结合可能是一种有效的抗癌策略。遗传学研究已经为这些机制提供了广泛的理解，但关于netrin信号传导受损导致人类疾病的情况仍有待发现。至关重要的是，netrin在细胞表面识别的细节（精细笔触）以及信息如何传递到细胞中的细节知之甚少。这种细节水平可以极大地帮助药物设计。我们的目标是通过提供netrin受体复合物的分子快照，使用X射线晶体学结合功能，生物物理和基于细胞的实验的方法来解开这些基本机制。我们的研究结果将通过与神经生物学家的合作放在神经系统和整个生物体的背景下，以获得综合的图像和更深入的理解。这将潜在地允许新的治疗和/或诊断方法的结构引导设计。

项目成果

Initiation of T cell signaling by CD45 segregation at 'close contacts'.

• DOI: 10.1038/ni.3392
• 发表时间: 2016-05
• 期刊: Nature immunology
• 影响因子: 30.5
• 作者: Chang VT;Fernandes RA;Ganzinger KA;Lee SF;Siebold C;McColl J;Jönsson P;Palayret M;Harlos K;Coles CH;Jones EY;Lui Y;Huang E;Gilbert RJC;Klenerman D;Aricescu AR;Davis SJ
• 通讯作者: Davis SJ

Calibration-free In Vitro Quantification of Protein Homo-oligomerization Using Commercial Instrumentation and Free, Open Source Brightness Analysis Software.

使用商业仪器和免费开源亮度分析软件对蛋白质同聚进行免校准体外定量。

• DOI: 10.3791/58157
• 发表时间: 2018
• 期刊: JoVE
• 作者: Nolan R

Structural basis for integration of GluD receptors within synaptic organizer complexes.

• DOI: 10.1126/science.aae0104
• 发表时间: 2016-07-15
• 期刊: Science (New York, N.Y.)
• 作者: Elegheert J;Kakegawa W;Clay JE;Shanks NF;Behiels E;Matsuda K;Kohda K;Miura E;Rossmann M;Mitakidis N;Motohashi J;Chang VT;Siebold C;Greger IH;Nakagawa T;Yuzaki M;Aricescu AR
• 通讯作者: Aricescu AR

RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling.

• DOI: 10.1016/j.tcb.2016.11.009
• 发表时间: 2017-05
• 期刊: Trends in cell biology
• 影响因子: 19
• 作者: Siebold C;Yamashita T;Monnier PP;Mueller BK;Pasterkamp RJ
• 通讯作者: Pasterkamp RJ

Simultaneous binding of Guidance Cues NET1 and RGM blocks extracellular NEO1 signaling.

• DOI: 10.1016/j.cell.2021.02.045
• 发表时间: 2021-04-15
• 期刊: Cell
• 影响因子: 64.5
• 作者: Robinson RA;Griffiths SC;van de Haar LL;Malinauskas T;van Battum EY;Zelina P;Schwab RA;Karia D;Malinauskaite L;Brignani S;van den Munkhof MH;Düdükcü Ö;De Ruiter AA;Van den Heuvel DMA;Bishop B;Elegheert J;Aricescu AR;Pasterkamp RJ;Siebold C
• 通讯作者: Siebold C