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Equilibrium Binding Model for CpG DNA-Dependent Dimerization of Toll-like Receptor 9 Ectodomain.
Biochemistry ( IF 2.9 ) Pub Date : 2020-08-20 , DOI: 10.1021/acs.biochem.0c00466 Stephanie Reikine 1, 2 , Stephen H McLaughlin 3 , Yorgo Modis 1, 2
Biochemistry ( IF 2.9 ) Pub Date : 2020-08-20 , DOI: 10.1021/acs.biochem.0c00466 Stephanie Reikine 1, 2 , Stephen H McLaughlin 3 , Yorgo Modis 1, 2
Affiliation
Microbial nucleic acids in the extracellular milieu are recognized in vertebrates by Toll-like receptors (TLRs), one of the most important families of innate immune receptors. TLR9 recognizes single-stranded unmethylated CpG DNA in endosomes. DNA binding induces TLR9 dimerization and activation of a potent inflammatory response. To provide insights on how DNA ligands induce TLR9 dimerization, we developed a detailed theoretical framework for equilibrium ligand binding, modeling the binding of the ssDNA at the two main sites on the TLR9 ectodomain. Light scattering and fluorescence anisotropy assays performed with recombinant TLR9 ectodomain and a panel of agonistic and antagonistic DNA ligands provide data that restrain the binding parameters, identify the likely ligand binding intermediates, and suggest cooperative modes of binding. This work brings us one step closer to establishing a rigorous biochemical understanding of how TLRs are activated by their ligands.
中文翻译:
Toll 样受体 9 胞外域 CpG DNA 依赖性二聚化的平衡结合模型。
细胞外环境中的微生物核酸在脊椎动物中被 Toll 样受体 (TLR) 识别,TLR 是最重要的先天免疫受体家族之一。TLR9 识别内体中的单链未甲基化 CpG DNA。DNA 结合诱导 TLR9 二聚化并激活有效的炎症反应。为了深入了解 DNA 配体如何诱导 TLR9 二聚化,我们开发了一个详细的平衡配体结合理论框架,模拟了 ssDNA 在 TLR9 胞外域的两个主要位点的结合。用重组 TLR9 胞外域和一组激动和拮抗 DNA 配体进行的光散射和荧光各向异性测定提供了限制结合参数的数据,识别可能的配体结合中间体,并建议结合的合作模式。
更新日期:2020-08-20
中文翻译:
Toll 样受体 9 胞外域 CpG DNA 依赖性二聚化的平衡结合模型。
细胞外环境中的微生物核酸在脊椎动物中被 Toll 样受体 (TLR) 识别,TLR 是最重要的先天免疫受体家族之一。TLR9 识别内体中的单链未甲基化 CpG DNA。DNA 结合诱导 TLR9 二聚化并激活有效的炎症反应。为了深入了解 DNA 配体如何诱导 TLR9 二聚化,我们开发了一个详细的平衡配体结合理论框架,模拟了 ssDNA 在 TLR9 胞外域的两个主要位点的结合。用重组 TLR9 胞外域和一组激动和拮抗 DNA 配体进行的光散射和荧光各向异性测定提供了限制结合参数的数据,识别可能的配体结合中间体,并建议结合的合作模式。