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/T000503/1
• 负责人: Yvonne Jones
• 金额: $ 213.87万
• 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: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT000503%2F1
• 关键词: Structural; Basis; Molecular; Mechanisms; Cell

The cells of a multicellular organism, such as a human, are 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.

多细胞生物体的细胞，如人类，在发育过程中会经历一场精致的舞蹈。每一个细胞都必须在发育中的有机体中的特定时间和地点实现与其作用相适应的粘附性和运动性之间的特定平衡。指导每个细胞的大部分信息必须通过与包括相邻细胞在内的直接环境的相互作用来获得。这些相互作用由嵌入细胞表面的各种类型的受体分子介导。我们希望了解一个分子家族，即信号蛋白，如何与它们的受体，即丛蛋白一起工作，以控制细胞粘附或向特定方向移动的能力。利用结构生物学的技术，我们的目标是揭示，在原子的细节，信号蛋白和丛蛋白控制细胞粘附和指导的机制，例如在指导大脑的布线。这些机制必须整合细胞之间和同一细胞表面上发生的受体相互作用，以及从细胞外环境到细胞内环境的跨越。为了深入了解这样的系统，我们将需要使用最先进的技术，以产生合适的样品的信号蛋白，丛蛋白和它们的复合物，并结合联合收割机在体外结构的分离分子的研究与原位分析在功能相关的背景下的细胞表面。这是对生物学构建神经系统和血管、维持骨骼和激活免疫系统的机制的基础研究。通过了解这些机制，我们也将更好地准备探索可能导致脊髓损伤后切断神经再生失败的分子因素，骨相关疾病，如骨质疏松症，神经发育障碍，如自闭症障碍谱，以及癌症。最终，生物技术和制药行业可以利用这些知识来为新型疗法的设计提供信息和指导。

项目成果

Author Correction: The guidance receptor plexin D1 is a mechanosensor in endothelial cells.

作者更正：引导受体丛蛋白 D1 是内皮细胞中的机械传感器。

• DOI: 10.1038/s41586-022-04815-w
• 发表时间: 2022
• 期刊: Nature
• 影响因子: 64.8
• 作者: Mehta V

Truncated-semaphorin3A is a potential regulatory molecule to restore immune homeostasis in immune-mediated diseases.

• DOI: 10.3389/fphar.2022.1085892
• 发表时间: 2022
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6

Primary and secondary functions of HLA-E are determined by stability and conformation of the peptide-bound complexes.

• DOI: 10.1016/j.celrep.2022.110959
• 发表时间: 2022-06-14
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Walters, Lucy C.;Rozbesky, Daniel;Harlos, Karl;Quastel, Max;Sun, Hong;Springer, Sebastian;Rambo, Robert P.;Mohammed, Fiyaz;Yvonne Jones, E.;McMichael, Andrew J.;Gillespie, Geraldine M.
• 通讯作者: Gillespie, Geraldine M.

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

Mouse and human antibodies bind HLA-E-leader peptide complexes and enhance NK cell cytotoxicity.

• DOI: 10.1038/s42003-022-03183-5
• 发表时间: 2022-03-28
• 期刊: Communications biology
• 影响因子: 5.9
• 作者: Li D;Brackenridge S;Walters LC;Swanson O;Harlos K;Rozbesky D;Cain DW;Wiehe K;Scearce RM;Barr M;Mu Z;Parks R;Quastel M;Edwards RJ;Wang Y;Rountree W;Saunders KO;Ferrari G;Borrow P;Jones EY;Alam SM;Azoitei ML;Gillespie GM;McMichael AJ;Haynes BF
• 通讯作者: Haynes BF