The Structural Basis of Molecular Mechanisms in Cell Guidance and Adhesion.

细胞引导和粘附分子机制的结构基础。

• 批准号: MR/M000141/1
• 负责人: Yvonne Jones
• 金额: $ 214.83万
• 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%2FM000141%2F1
• 关键词: Structural; Basis; Molecular; Mechanisms; Cell

The cells of a multicellular organism, such as a human, must be subject to an exquisite choreography during development. Each cell must achieve the particular balance between adhesion and motility appropriate to its role at a specific time and place in the developing organism. Much of the information to direct each cell must be garnered through interaction with its immediate environment including neighbouring cells. These interactions are mediated by various types of receptor molecules embedded in the cell surface. We wish to understand how one family of molecules, the semaphorins, work together with their receptors, the plexins, to control the ability of a cell to stick (adhere) or to move in a specific direction. Using the techniques of structural biology we aim to uncover, in atomic detail, the mechanisms by which the semaphorins and plexins control cell adhesion and guidance, for example in directing the wiring of the brain. These mechanisms must integrate receptor interactions occurring between cells and on the same cell surface, as well as spanning from the extracellular to the intracellular environment. To generate insight into such systems we will need to use state of the art techniques to produce suitable samples of the semaphorins, the plexins and their complexes, and to combine in vitro structural studies on the isolated molecules with in situ analyses in the functionally relevant context of the cell surface. This is basic research into the mechanisms by which biology works to build the nervous system and the blood vessels, to maintain bones and to activate the immune system. By understanding these mechanisms we will also be better equipped to explore molecular factors which may contribute to the failure of severed nerves to regenerate following spinal cord injury, to bone-related disorders, for example osteoporosis, to neurodevelopmental disorders such as autism disorder spectrum, and to cancer. Ultimately this knowledge can be used by the biotechnology and pharmaceutical industries, to inform and guide the design of novel therapeutics.

多细胞生物（如人类）的细胞在发育过程中必须经过精心设计。每个细胞都必须在黏附性和运动性之间达到特定的平衡，以适应其在发育生物体中的特定时间和地点的作用。指导每个细胞的大部分信息必须通过与其直接环境（包括邻近细胞）的相互作用来获得。这些相互作用是由嵌入细胞表面的各种类型的受体分子介导的。我们希望了解一个分子家族，即信号素，是如何与它们的受体丛蛋白一起工作，以控制细胞粘附或向特定方向移动的能力的。利用结构生物学的技术，我们的目标是在原子细节上揭示信号蛋白和丛蛋白控制细胞粘附和引导的机制，例如指导大脑的连接。这些机制必须整合发生在细胞之间和同一细胞表面上的受体相互作用，以及从细胞外到细胞内环境的跨越。为了深入了解这样的系统，我们需要使用最先进的技术来生产信号蛋白、丛蛋白及其复合物的合适样品，并将分离分子的体外结构研究与细胞表面功能相关背景下的原位分析相结合。这是一项基础研究，研究生物如何构建神经系统和血管、维持骨骼和激活免疫系统。通过了解这些机制，我们也将更好地探索可能导致脊髓损伤后切断的神经再生失败的分子因素，骨质疏松症等骨相关疾病，自闭症谱系障碍等神经发育障碍，以及癌症。最终，这些知识可以用于生物技术和制药行业，为新疗法的设计提供信息和指导。

项目成果

The guidance and adhesion protein FLRT2 dimerizes in cis via dual small-X3-small transmembrane motifs.

引导和粘附蛋白 FLRT2 通过双小 X3 小跨膜基序顺式二聚化。

• DOI: 10.1016/j.str.2022.05.014
• 发表时间: 2022
• 期刊: 1993)
• 作者: Jackson V

Structural basis of latrophilin-FLRT interaction.

• DOI: 10.1016/j.str.2015.01.013
• 发表时间: 2015-04-07
• 期刊: STRUCTURE
• 影响因子: 5.7
• 作者: Jackson, Verity A.;del Toro, Daniel;Carrasquero, Maria;Roversi, Pietro;Harlos, Karl;Klein, Ruediger;Seiradake, Elena
• 通讯作者: Seiradake, Elena

Structural Basis for Plexin Activation and Regulation.

• DOI: 10.1016/j.neuron.2016.06.018
• 发表时间: 2016-08-03
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Kong Y;Janssen BJ;Malinauskas T;Vangoor VR;Coles CH;Kaufmann R;Ni T;Gilbert RJ;Padilla-Parra S;Pasterkamp RJ;Jones EY
• 通讯作者: Jones EY

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

Understanding cell signalling systems: paving the way for new therapies.

• DOI: 10.1098/rsta.2013.0155
• 发表时间: 2015-03-06
• 期刊: Philosophical transactions. Series A, Mathematical, physical, and engineering sciences
• 作者: Jones EY