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首页> 外文期刊>Biochemistry >Murine Interleukin-3: Structure, Dynamics, and Conformational Heterogeneity in Solution
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Murine Interleukin-3: Structure, Dynamics, and Conformational Heterogeneity in Solution

机译：鼠白细胞介素-3：溶液中的结构，动力学和构象异质性

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摘要

Interleukin-3 (IL-3), a cytokine produced primarily by activated T-cells during immune responses, is a crucial regulator of allergic inflammation. The three-dimensional structure of murine IL-3 (mIL-3) has remained elusive owing to its poor solubility and strong tendency toward aggregation under solution conditions typically used for structural studies. Here we describe the solution properties and structure of mIL-3 determined by NMR using an engineered construct of mIL-3 (mIL-3(33-156)). mIL-3 adopts a four-helical bundle fold, typical of proteins belonging to the short-chain cytokine family, and features a core of highly conserved hydrophobic residues. While significant line broadening and peak disappearance were observed in NMR spectra at higher temperatures, there was no evidence for temperature-dependent changes of the oligomeric state of mIL-3(33-156). Further analysis of the temperature dependence of amide H-1 chemical shifts and backbone N-15 relaxation parameters, including 15N relaxation dispersion, revealed the presence of significant conformational exchange and local conformational heterogeneity. Residues recently shown by mutagenesis to play key roles in beta(IL-3) receptor recognition and activation, which are located within the alpha(A) and alpha(C) helices and aligned on one face of the mIL-3(33-156) structure, are relatively rigid. In contrast, pronounced conformational heterogeneity was observed for a cluster of residues located on the opposite side of mIL-3, which corresponds spatially to sites in the related cytokines human IL-3, IL-5, and GM-CSF that are known to mediate interactions with their respective alpha-receptor subunits. Such conformational heterogeneity may facilitate the interaction of mIL-3 with each of two naturally occurring mIL-3R alpha isoforms, leading to structurally distinct high-affinity complexes.
机译：白细胞介素-3（IL-3），一种主要由活性T细胞产生的细胞因子，在免疫反应期间是过敏性炎症的关键调节因子。由于其在通常用于结构研究的溶液条件下，鼠IL-3（MIL-3）的三维结构仍然难以难以实现。在这里，我们描述了使用MIL-3的工程构造（MIL-3（33-156））通过NMR确定的MIL-3的溶液性能和结构。 MIL-3采用四螺旋束折叠，典型的蛋白质属于短链细胞因子家族，并具有高度保守的疏水残留的核心。虽然在较高温度下在NMR光谱中观察到显着的线条扩大和峰值消失，但没有证据依赖于MIL-3（33-156）的低聚状态的变化。进一步分析酰胺H-1化学位移和骨干N-15弛豫参数的温度依赖性，包括15N松弛分散，揭示了显着的构象交换和局部构象异质性的存在。最近通过诱变显示的残留物，以在β（IL-3）受体识别和激活中发挥关键作用，其位于α（a）和α（c）螺旋内，并在MIL-3的一张面上对齐（33-156 ）结构，相对刚性。相反，对于位于MIL-3的相对侧的残基簇中观察到明显的构象异质性，其在空间上对应于相关细胞因子人IL-3，IL-5和GM-CSF中已知的介导的网站与各自的α受体亚基相互作用。这种构象的异质性可以促进MIL-3与两个天然存在的MIL-3Rα同种型中的每一种相互作用，导致结构上不同的高亲和力络合物。

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  • 来源
    《Biochemistry》 |2011年第13期|共14页
  • 作者

    Yao SG; Young IG; Norton RS; Murphy JM;

  • 作者单位

    The Walter and Eliza Hall Institute of Medical Research 1G Royal Parade Parkville Victoria 3052 Australia;

    John Curtin School of Medical Research Australian National University Canberra Australian Capital Territory 0200 Australia;

    The Walter and Eliza Hall Institute of Medical Research 1G Royal Parade Parkville Victoria 3052 Australia;

    The Walter and Eliza Hall Institute of Medical Research 1G Royal Parade Parkville Victoria 3052 Australia;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;
  • 关键词

    Murine Interleukin; Dynamics; Solution;

    机译：鼠白细胞介素;动态;解决方案;

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