Evolutionary, structural and functional interplay of the IκB family members.
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.
Department of Molecular Science and Technology, Ajou University, Suwon, Korea.
Shaherin
S
Basith
Balachandran
B
Manavalan
Vijayakumar
V
Gosu
Sangdun
S
Choi
D000595:Amino Acid Sequence; D000818:Animals; D001499:Bayes Theorem; D004331:Drosophila melanogaster / Q000235:genetics; D019143:Evolution, Molecular; D006801:Humans; D020672:I-kappa B Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D007448:Invertebrates / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010802:Phylogeny; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D020569:Proto-Oncogene Proteins c-rel / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012641:Selection, Genetic; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014714:Vertebrates / Q000235:genetics*
D020672:I-kappa B Proteins; D016328:NF-kappa B; D020033:Protein Isoforms; D020569:Proto-Oncogene Proteins c-rel