talin自身抑制状态的高分辨率快照表明其在细胞粘附和信号传导中的作用-动脉网

High-resolution snapshots of the talin auto-inhibitory states suggest roles in cell adhesion and signaling

Nature 等信源发布 2024-10-28 16:57

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AbstractTalin regulates crucial cellular functions, including cell adhesion and motility, and affects human diseases. Triggered by mechanical forces, talin plays crucial roles in facilitating the formation of focal adhesions and recruiting essential focal adhesion regulatory elements such as vinculin.

Abstractalin调节关键的细胞功能，包括细胞粘附和运动，并影响人类疾病。由机械力触发，塔林在促进粘着斑的形成和募集重要的粘着斑调节元件（如纽蛋白）方面起着至关重要的作用。

The structural flexibility allows talin to fine-tune its signaling responses. This study presents our 2.7 Å cryoEM structures of talin, which surprisingly uncovers several auto-inhibitory states. Contrary to previous suggestions, our structures reveal that (1) the first and last three domains are not involved in maintaining talin in its closed state and are mobile, (2) the talin F-actin and membrane binding domain are loosely attached and thus available for binding, and (3) the main force-sensing domain is oriented with its vinculin binding sites ready for release.

结构的灵活性允许talin微调其信号响应。这项研究介绍了我们的talin的2.7ÅcryoEM结构，令人惊讶地揭示了几种自抑制状态。与之前的建议相反，我们的结构显示（1）前三个结构域和后三个结构域不参与维持talin处于闭合状态并且是可移动的，（2）talin F-肌动蛋白和膜结合结构域松散连接，因此可用于结合，以及（3）主要的力感应结构域以其纽蛋白结合位点定向，准备释放。

These structural snapshots offer insights and advancements in understanding the dynamic talin activation mechanism, which is crucial for mediating cell adhesion..

。。

IntroductionTalin plays an indispensable role in cell motility and migration by modulating the dynamics of focal adhesions1. Talin facilitates cellular attachment to the extracellular matrix by activating the transmembrane integrin receptors. This binding induces a structural transformation in both integrin polypeptide chains, enhancing integrin in engaging with extracellular matrix ligands2.

引言Talin通过调节粘着斑的动力学在细胞运动和迁移中起着不可或缺的作用1。Talin通过激活跨膜整联蛋白受体促进细胞与细胞外基质的附着。这种结合诱导两条整联蛋白多肽链的结构转化，增强整联蛋白与细胞外基质配体的结合2。

This activation is critical for cell adhesion and downstream signaling processes that regulate cell growth, survival, and differentiation. Consequently, it is unsurprising that talin is essential for tissue morphogenesis and organogenesis.Moreover, talin contributes to immune responses by promoting the adhesion of immune cells, such as T cells and neutrophils, to blood vessel walls, thereby enabling their migration to sites of infection or inflammation3.

这种激活对于调节细胞生长，存活和分化的细胞粘附和下游信号传导过程至关重要。因此，毫不奇怪，塔林对于组织形态发生和器官发生至关重要。此外，talin通过促进免疫细胞（如T细胞和嗜中性粒细胞）与血管壁的粘附来促进免疫反应，从而使其能够迁移到感染或炎症部位3。

Dysregulation of talin function has been implicated in a spectrum of diseases4,5, including cancer4,5,6,7,8, cardiovascular disorders5,9,10, and autoimmune conditions. A deeper understanding of the involvement of talin in these diseases offers promising avenues for potential therapeutic interventions.The talin polypeptide chain, consisting of 2541 amino acids, is organized into an amino-terminal head and a carboxy-terminal tail domain connected by approximately eighty residues, which act as a flexible linker11,12,13 (Fig. 1a).

塔林功能失调与一系列疾病有关，包括癌症4,5,6,7,8，心血管疾病5,9,10和自身免疫性疾病。对塔林参与这些疾病的深入了解为潜在的治疗干预提供了有希望的途径。由2541个氨基酸组成的塔林多肽链被组织成一个氨基末端头部和一个羧基末端尾部结构域，该结构域由大约80个残基连接，充当柔性接头11,12,13（图1a）。

The head domain features a distinctive FERM (4.1 protein, ezrin, radixin, moesin) configuration that exhibits the classical FERM subdomains (F1-F3) arranged linearly instead of resembling a cloverleaf, with an additional insertion in F1 and a unique subdomain at the outset, F014 (PDB entries 3ivf15, 6mfs16).

头部结构域具有独特的FERM（4.1蛋白，ezrin，radixin，moesin）构型，其表现出线性排列的经典FERM亚结构域（F1-F3），而不是类似于三叶草，在F1中有额外的插入，并且在一开始就有一个独特的亚结构域F014（PDB条目3ivf15，6mfs16）。

SAXS analyses supported the extended conformation of the FERM domain. However, SAXS also indicated add.

SAXS分析支持FERM域的扩展构象。但是，SAXS也表示添加。

Data availability

数据可用性

The final coordinates and the Coulomb potential maps generated in this study for the talin2.7 (PDB entry 8vdo; EMD-43152), talin3.4 (8vdp; EMD-43154), talin5.5 (8vdq; EMD-43155), and talin3.7 (8vdr; EMD-43156) structures have been deposited with the Protein Data Bank and Electron Microscopy Data Bank, respectively.

本研究中生成的talin2.7（PDB条目8vdo；EMD-43152），talin3.4（8vdp；EMD-43154），talin5.5（8vdq；EMD-43155）和talin3.7（8vdr；EMD-43156）结构的最终坐标和库仑电位图已分别存放在蛋白质数据库和电子显微镜数据库中。

The Coulomb potential map for talin3.39 was deposited with EMDB (accession code EMD-44931). The raw movies for both datasets are accessible through accession codes EMPIAR-11881 (talin5.5 and talin3.7 [https://www.ebi.ac.uk/empiar/EMPIAR-11881]) and EMPIAR-11882 (talin2.7, talin3.4, and talin3.39 [https://www.ebi.ac.uk/empiar/EMPIAR-11882]).

talin3.39的库仑电位图已保存在EMDB（登录号EMD-44931）中。这两个数据集的原始电影都可以通过登录号EMPIAR-11881（talin5.5和talin3.7）访问[https://www.ebi.ac.uk/empiar/EMPIAR-11881])和EMPIAR-11882（talin2.7、talin3.4和talin3.39[https://www.ebi.ac.uk/empiar/EMPIAR-11882])。

The expression plasmid is available with Addgene (ID #164838 [https://www.addgene.org/164838/]). Source data are provided with this paper..

表达质粒可与Addgene（ID#164838）一起获得[https://www.addgene.org/164838/])。本文提供了源数据。。

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Download referencesAcknowledgementsTI is grateful for the support from grants from the National Institutes of Health (R35 GM139604) and the National Science Foundation (2030119) and start-up funds provided to The Scripps Research Institute by the State of Florida. We are deeply indebted to Drs Ben Goult (University of Liverpool, United Kingdom) and Daniel Lietha (Biological Research Center Margarita Salas, CIB-CSIC, Spain) for countless insightful discussions.Author informationAuthors and AffiliationsCell Adhesion Laboratory, UF Scripps, Jupiter, FL, USAErumbi S.

下载参考文献致谢感谢美国国立卫生研究院（R35 GM139604）和国家科学基金会（2030119）的资助以及佛罗里达州向斯克里普斯研究所提供的启动资金。我们非常感谢Ben Goult博士（英国利物浦大学）和Daniel Lietha（西班牙CIB-CSIC玛格丽塔萨拉斯生物研究中心）进行了无数有见地的讨论。作者信息作者和附属机构细胞粘附实验室，UF Scripps，Jupiter，FL，USAErumbi S。

Rangarajan & Tina IzardDepartment of Molecular Medicine, UF Scripps, Jupiter, FL, USAErumbi S. Rangarajan, Julian L. Bois, Scott B. Hansen & Tina IzardThe Skaggs Graduate School, The Scripps Research Institute, La Jolla, CA, USAScott B. Hansen & Tina IzardAuthorsErumbi S. RangarajanView author publicationsYou can also search for this author in.

Rangarajan＆Tina IzardDepartment of Molecular Medicine，UF Scripps，Jupiter，FL，USAErumbi S.Rangarajan，Julian L.Bois，Scott B.Hansen＆Tina IzardThe Skaggs Graduate School，The Scripps Research Institute，La Jolla，CA，USAScott B.Hansen＆Tina IzardAuthorsErumbi S.RangarajanView author Publications你也可以在中搜索这位作者。

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PubMed Google ScholarContributionsE.S.R. and T.I. contributed to all stages of the manuscript. S.B.H. designed the dSTORM experiments with mechanical force, analyzed the data, and helped write the manuscript. J.B. performed the talin-GFP expression, fluorescent labeling, and acquisition of the dSTORM data.Corresponding authorCorrespondence to.

PubMed谷歌学术贡献。S、 R.和T.I.为稿件的所有阶段做出了贡献。S、 B.H.用机械力设计了dSTORM实验，分析了数据，并帮助撰写了手稿。J、 B.进行了talin-GFP表达，荧光标记和dSTORM数据的获取。对应作者对应。

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Reprints and permissionsAbout this articleCite this articleRangarajan, E.S., Bois, J.L., Hansen, S.B. et al. High-resolution snapshots of the talin auto-inhibitory states suggest roles in cell adhesion and signaling.

转载和许可本文引用本文Rangarajan，E.S.，Bois，J.L.，Hansen，S.B.等人。talin自抑制状态的高分辨率快照表明在细胞粘附和信号传导中的作用。

Nat Commun 15, 9270 (2024). https://doi.org/10.1038/s41467-024-52581-2Download citationReceived: 23 January 2024Accepted: 12 September 2024Published: 28 October 2024DOI: https://doi.org/10.1038/s41467-024-52581-2Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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