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首页> 外文期刊>Open Biology >Solution structure of CXCL13 and heparan sulfate binding show that GAG binding site and cellular signalling rely on distinct domains
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Solution structure of CXCL13 and heparan sulfate binding show that GAG binding site and cellular signalling rely on distinct domains

机译：CXCL13和硫酸乙酰肝素结合的溶液结构表明，GAG结合位点和细胞信号传导依赖于不同的结构域

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Chemokines promote directional cell migration through binding to G-protein-coupled receptors, and as such are involved in a large array of developmental, homeostatic and pathological processes. They also interact with heparan sulfate (HS), the functional consequences of which depend on the respective location of the receptor- and the HS-binding sites, a detail that remains elusive for most chemokines. Here, to set up a biochemical framework to investigate how HS can regulate CXCL13 activity, we solved the solution structure of CXCL13. We showed that it comprises an unusually long and disordered C-terminal domain, appended to a classical chemokine-like structure. Using three independent experimental approaches, we found that it displays a unique association mode to HS, involving two clusters located in the α-helix and the C-terminal domain. Computational approaches were used to analyse the HS sequences preferentially recognized by the protein and gain atomic-level understanding of the CXCL13 dimerization induced upon HS binding. Starting with four sets of 254 HS tetrasaccharides, we identified 25 sequences that bind to CXCL13 monomer, among which a single one bound to CXCL13 dimer with high consistency. Importantly, we found that CXCL13 can be functionally presented to its receptor in a HS-bound form, suggesting that it can promote adhesion-dependent cell migration. Consistently, we designed CXCL13 mutations that preclude interaction with HS without affecting CXCR5-dependent cell signalling, opening the possibility to unambiguously demonstrate the role of HS in the biological function of this chemokine.
机译：趋化因子通过与G蛋白偶联受体结合而促进定向细胞迁移，因此参与许多发育，体内平衡和病理过程。它们还与硫酸乙酰肝素（HS）相互作用，其功能后果取决于受体结合位点和HS结合位点的相应位置，这一细节对于大多数趋化因子仍然难以捉摸。在这里，为了建立一个生化框架来研究HS如何调节CXCL13活性，我们解决了CXCL13的溶液结构。我们表明它包含一个异常长且无序的C末端域，附加到经典的趋化因子样结构。使用三种独立的实验方法，我们发现它显示出与HS独特的关联模式，涉及位于α-螺旋和C端域的两个簇。使用计算方法来分析蛋白质优先识别的HS序列，并获得HS结合诱导的CXCL13二聚化的原子水平理解。从四组254个HS四糖开始，我们鉴定了25个与CXCL13单体结合的序列，其中一个序列与CXCL13二聚体具有很高的一致性。重要的是，我们发现CXCL13可以功能上呈HS结合形式存在于其受体，表明它可以促进粘附依赖性细胞迁移。一致地，我们设计了在不影响CXCR5依赖性细胞信号转导的情况下排除与HS相互作用的CXCL13突变，从而为明确证明HS在该趋化因子生物学功能中的作用提供了可能性。

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