Department of Molecular Science and Technology, Ajou University, Suwon, Korea.
PLoS One. 2013;8(1):e54178. doi: 10.1371/journal.pone.0054178. Epub 2013 Jan 23.
A primary level of control for nuclear factor kappa B (NF-κB) is effected through its interactions with the inhibitor protein, inhibitor of kappa B (IκB). Several lines of evidence confirm the existence of multiple forms of IκB that appear to regulate NF-κB by distinct mechanisms. Therefore, we performed a comprehensive bioinformatics analysis to understand the evolutionary history and intrinsic functional diversity of IκB family members. Phylogenetic relationships were constructed to trace the evolution of the IκB family genes. Our phylogenetic analysis revealed 10 IκB subfamily members that clustered into 5 major clades. Since the ankyrin (ANK) domain appears to be more ancient than the Rel homology domain (RHD), our phylogenetic analysis suggests that some undefined ancestral set of ANK repeats acquired an RHD before any duplication and was later duplicated and then diverged into the different IκB subfamilies. Functional analysis identified several functionally divergent sites in the ANK repeat domains (ARDs) and revealed that this region has undergone strong purifying selection, suggesting its functional importance in IκB genes. Structural analysis showed that the major variations in the number of ANK repeats and high conformational changes in the finger loop ARD region contribute to the differing binding partner specificities, thereby leading to distinct IκB functions. In summary, our study has provided useful information about the phylogeny and structural and functional divergence of the IκB family. Additionally, we identified a number of amino acid sites that contribute to the predicted functional divergence of these proteins.
NF-κB 的一个主要调控层次是通过其与抑制蛋白 IκB 的相互作用来实现的。有几条证据证实存在多种形式的 IκB,它们似乎通过不同的机制来调节 NF-κB。因此,我们进行了全面的生物信息学分析,以了解 IκB 家族成员的进化历史和内在功能多样性。构建了系统发育关系来追踪 IκB 家族基因的进化。我们的系统发育分析揭示了 10 个 IκB 亚家族成员,它们聚集成 5 个主要分支。由于锚蛋白(ANK)结构域似乎比 Rel 同源结构域(RHD)更古老,我们的系统发育分析表明,在任何重复之前,一组未定义的祖先 ANK 重复获得了 RHD,然后重复并随后分化为不同的 IκB 亚家族。功能分析确定了 ANK 重复结构域(ARD)中的几个功能分化位点,并揭示该区域经历了强烈的纯化选择,表明其在 IκB 基因中的功能重要性。结构分析表明,ANK 重复数的主要变化和指环 ARD 区域的高构象变化导致了不同的结合伴侣特异性,从而导致了不同的 IκB 功能。总之,我们的研究为 IκB 家族的系统发育、结构和功能分化提供了有用的信息。此外,我们确定了一些氨基酸位点,这些位点有助于预测这些蛋白质的功能分化。