Structural studies on the talin head domain - a key regulator of cell-matrix interactions
talin头域的结构研究——细胞-基质相互作用的关键调节因子
基本信息
- 批准号:BB/G003637/1
- 负责人:
- 金额:$ 56.3万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2009
- 资助国家:英国
- 起止时间:2009 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
In all multi-cellular organisms cells are attached to a special tissue, extracellular matrix. This establishes the integrity of the organism and shapes other tissues, making cell-matrix interaction essential for the embryonic development and tissue maintenance. The cells are attached to the matrix through integrin receptors that are embedded in the outer cell membrane. A large multi-protein adhesion complexes are formed at the intra-cellular domains of the receptors connecting receptors to the cytoskeleton that maintains the shape and rigidity of cells. In moving a cell the contacts with the matrix are established through a series of connected events. At the leading edge the cell engages layilin receptors to establish initial contacts. Inside the cell an adaptor protein talin is recruited to the site of the adhesion. Talin, in turn, binds and activates PIP kinase that generates signalling molecule PIP2 at the site of the adhesion. In addition, talin activates integrin receptors that are required for a strong contact. Talin also makes a connection the between the receptors and actin cytoskeleton that allows the cell to apply force required for the motion. The main challenge when studying such a complex system is to derive a comprehensive information that takes all components into account. In order to achieve this we have chosen a key protein of the adhesion complex - talin and devised a set of experiments using various biophysical methods to analyse the network of interactions that talin forms at different stages of adhesion. We aim at extracting the main factors that direct and regulate talin interaction to analyse them in depth and then to integrate this knowledge within a single model that can be tested experimentally. We concentrate on the head domain of this large 2541-residue protein as it is crucial for the interaction with integrin and layilin receptors and contains binding sites for PIP kinase and PIP2. This 400-residue fragment consists of four well-defined subdomains and our preliminary data indicate that the relative orientation of the subdomains may depend on the protein environment, providing a mechanism for the activity regulation. Initially we will determine the structure of the full talin head and analyse the factors that affect it. We will then introduce talin ligands and determine the contribution from different parts of the talin head into the interactions. We expect that some of the subdomains will be involved in direct contact, while others will contribute indirectly by affecting the binding domains. We will also study the effect of binding of one ligand on the talin interaction with a different ligand. This information is essential for the understanding of how one talin ligand displaces another during the adhesion complex assembly. Despite of the importance for the adhesion regulation, talin interaction with PIP2 remains elusive due to the low stability of the complex. We found conditions for the PIP2 complex analysis in our pilot studies and will determine the effect of PIP2 binding on talin structure in order to understand the mechanism of talin activation by PIP2. As the adhesion complexes are assembled on a membrane, the understanding of the system is incomplete until the effect of the membrane is determined. We will derive conditions that will allow us to obtain structural information in a membrane-like environment and will use them to reconstitute the talin adhesion complexes. This will bring all the main components together and will provide an experimental model for the integrated analysis of the talin function. We will use the model to design talin mutations that selectively enhance specific interactions so they can be correlated with the biological properties in cell experiments.
在所有多细胞生物体中,细胞都附着在特殊的组织,即细胞外基质上。这建立了生物体的完整性并塑造其他组织,使细胞-基质相互作用对于胚胎发育和组织维持至关重要。细胞通过嵌入细胞外膜的整合素受体附着在基质上。在受体的细胞内结构域形成大型多蛋白粘附复合物,将受体连接到维持细胞形状和刚性的细胞骨架。在移动细胞时,通过一系列相关事件建立与矩阵的接触。在前缘,细胞与layilin受体结合以建立初始接触。在细胞内部,接头蛋白踝蛋白被募集到粘附位点。 Talin 反过来结合并激活 PIP 激酶,在粘附部位生成信号分子 PIP2。此外,talin 还能激活强接触所需的整合素受体。 Talin 还在受体和肌动蛋白细胞骨架之间建立了联系,使细胞能够施加运动所需的力。研究如此复杂的系统时的主要挑战是获取考虑所有组件的综合信息。为了实现这一目标,我们选择了粘附复合物的关键蛋白 - talin,并使用各种生物物理方法设计了一组实验来分析 talin 在粘附的不同阶段形成的相互作用网络。我们的目标是提取指导和调节talin相互作用的主要因素,对其进行深入分析,然后将这些知识整合到可以进行实验测试的单个模型中。我们重点关注这个含有 2541 个残基的大蛋白的头部结构域,因为它对于与整合素和 Layilin 受体的相互作用至关重要,并且包含 PIP 激酶和 PIP2 的结合位点。这个 400 个残基的片段由四个明确的子结构域组成,我们的初步数据表明,子结构域的相对方向可能取决于蛋白质环境,从而提供了活性调节的机制。首先,我们将确定全踝头的结构并分析影响它的因素。然后,我们将引入踝关节配体并确定踝关节头的不同部分对相互作用的贡献。我们预计一些子域将参与直接接触,而其他子域将通过影响结合域来间接做出贡献。我们还将研究一种配体的结合对踝蛋白与另一种配体相互作用的影响。这一信息对于理解粘附复合物组装过程中一种踝蛋白配体如何取代另一种配体至关重要。尽管talin对于粘附调节很重要,但由于复合物的稳定性较低,talin与PIP2的相互作用仍然难以捉摸。我们在初步研究中找到了 PIP2 复合物分析的条件,并将确定 PIP2 结合对踝蛋白结构的影响,以了解 PIP2 激活踝蛋白的机制。由于粘附复合物组装在膜上,因此在确定膜的作用之前,对系统的理解是不完整的。我们将推导出使我们能够在类膜环境中获得结构信息的条件,并使用它们来重建talin粘附复合物。这将把所有主要组成部分结合在一起,并为talin功能的集成分析提供一个实验模型。我们将使用该模型来设计踝蛋白突变,选择性地增强特定的相互作用,以便它们可以与细胞实验中的生物学特性相关联。
项目成果
期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The Structure of the talin head reveals a novel extended conformation of the FERM domain.
talin 头的结构揭示了 FERM 结构域的新型扩展构象。
- DOI:http://dx.10.1016/j.str.2010.07.011
- 发表时间:2010
- 期刊:
- 影响因子:0
- 作者:Elliott PR
- 通讯作者:Elliott PR
The domain structure of talin: residues 1815-1973 form a five-helix bundle containing a cryptic vinculin-binding site.
talin 的结构域结构:残基 1815-1973 形成包含隐秘纽蛋白结合位点的五螺旋束。
- DOI:http://dx.10.1016/j.febslet.2010.04.028
- 发表时间:2010
- 期刊:
- 影响因子:3.5
- 作者:Goult BT
- 通讯作者:Goult BT
RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover.
RIAM 和纽蛋白与踝蛋白的结合是相互排斥的,并且调节粘附组装和周转。
- DOI:http://dx.10.1074/jbc.m112.438119
- 发表时间:2013
- 期刊:
- 影响因子:0
- 作者:Goult BT
- 通讯作者:Goult BT
Central Region of Talin Has a Unique Fold That Binds Vinculin and Actin
Talin 的中央区域有一个独特的折叠,可以结合纽蛋白和肌动蛋白
- DOI:10.1074/jbc.m109.095455
- 发表时间:2010-09-17
- 期刊:
- 影响因子:0
- 作者:Gingras AR;Bate N;Goult BT;Patel B;Kopp PM;Emsley J;Barsukov IL;Roberts GC;Critchley DR
- 通讯作者:Critchley DR
Structure of a double ubiquitin-like domain in the talin head: a role in integrin activation.
talin 头中双泛素样结构域的结构:在整合素激活中的作用。
- DOI:http://dx.10.1038/emboj.2010.4
- 发表时间:2010
- 期刊:
- 影响因子:0
- 作者:Goult BT
- 通讯作者:Goult BT
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Igor Barsukov其他文献
Exploration of expanded carbohydrate chemical space to access biological activity using microwave-induced acid condensation of simple sugars
- DOI:
10.1039/d2ra01463g - 发表时间:
2022-04 - 期刊:
- 影响因子:3.9
- 作者:
James Andrew London;Sarah Louise Taylor;Igor Barsukov;Alan Cartmell;Edwin Alexander Yates - 通讯作者:
Edwin Alexander Yates
Dock-and-lock binding of SxIP ligands is required for stable and selective EB1 interactions
SxIP 配体的对接锁结合是稳定和选择性 EB1 相互作用所必需的
- DOI:
10.1101/2024.02.27.581919 - 发表时间:
2024-02-29 - 期刊:
- 影响因子:0
- 作者:
Teresa Almeida;Eleanor Hargreaves;Tobias Zech;Igor Barsukov - 通讯作者:
Igor Barsukov
Mechanosensing through talin 1 contributes to tissue mechanical homeostasis
通过talin 1进行机械传感有助于组织机械稳态
- DOI:
10.1101/2023.09.03.556084 - 发表时间:
2024-01-26 - 期刊:
- 影响因子:0
- 作者:
Manasa Ch;uri;uri;Abhishek Kumar;D. Weiss;Nir Emuna;Igor Barsukov;Muisi Shi;Keiichiro Tanaka;Xinzhe Wang;A. Datye;Jean Kanyo;Florine Collin;Tukiet T. Lam;Udo D. Schwarz;Suxia Bai;Timothy Nottoli;B. Goult;J. Humphrey;Martin A. Schwartz - 通讯作者:
Martin A. Schwartz
The 2024 magnonics roadmap
2024 年 Magnonics 路线图
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Benedetta Flebus;Dirk Grundler;B. Rana;Yoshichika Otani;Igor Barsukov;Anjan Barman;G. Gubbiotti;Pedro Landeros;J. Åkerman;Ursula S Ebels;P. Pirro;V. E. Demidov;Katrin Schultheiss;Gyorgy Csaba;Qi Wang;Dmitri E. Nikonov;F. Ciubotaru;Ping Che;Riccardo Hertel;T. Ono;Dmytro Afanasiev;J. Mentink;Theo Rasing;B. Hillebrands;Silvia Viola Kusminskiy;Wei Zhang;C. Du;A. Finco;T. van der Sar;Yunqiu Kelly Luo;Y. Shiota;J. Sklenar;Tao Yu;Jinwei Rao - 通讯作者:
Jinwei Rao
Spin torque ferromagnetic resonance with magnetic field modulation
具有磁场调制的自旋扭矩铁磁共振
- DOI:
10.1063/1.4826927 - 发表时间:
2013-10-21 - 期刊:
- 影响因子:4
- 作者:
A. M. Gonçalves;Igor Barsukov;Y. Chen;Liu Yang;J. Katine;I. Krivorotov - 通讯作者:
I. Krivorotov
Igor Barsukov的其他文献
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{{ truncateString('Igor Barsukov', 18)}}的其他基金
How tensins transform focal adhesions into fibrillar adhesions and phase separate to form new adhesion signalling hubs.
张力蛋白如何将粘着斑转化为纤维状粘连并相分离以形成新的粘连信号中枢。
- 批准号:
BB/Y005414/1 - 财政年份:2024
- 资助金额:
$ 56.3万 - 项目类别:
Research Grant
Development of a biotechnology platform for enzymatic sulfation of industrial products based on polysaccharide sulfotransferases
基于多糖磺基转移酶的工业产品酶促硫酸化生物技术平台的开发
- 批准号:
BB/V003372/1 - 财政年份:2020
- 资助金额:
$ 56.3万 - 项目类别:
Research Grant
Spin torque devices driven by tailored spin currents
由定制自旋电流驱动的自旋扭矩装置
- 批准号:
1810541 - 财政年份:2018
- 资助金额:
$ 56.3万 - 项目类别:
Standard Grant
SBIR Phase I: New and Improved Zinc-Air Battery System and Devices
SBIR第一阶段:新型和改进的锌空气电池系统和设备
- 批准号:
1248895 - 财政年份:2013
- 资助金额:
$ 56.3万 - 项目类别:
Standard Grant
Myosin II dynamics and the influence of S100A4
肌球蛋白 II 动力学和 S100A4 的影响
- 批准号:
BB/F007213/1 - 财政年份:2008
- 资助金额:
$ 56.3万 - 项目类别:
Research Grant
Role of the paxillin/poly(A)-binding protein 1 complex in mRNA trafficking during cell migration
桩蛋白/多聚腺苷酸结合蛋白 1 复合物在细胞迁移过程中 mRNA 运输中的作用
- 批准号:
BB/C003527/2 - 财政年份:2006
- 资助金额:
$ 56.3万 - 项目类别:
Research Grant
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