Journal
PLOS ONE
Volume 5, Issue 12, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0015782
Keywords
-
Categories
Funding
- Ministry of Education, Science and Technology [2010-0015356]
- Korea Food and Drug Administration [10182KFDA992]
- NRF of Korea [2009-0093826]
- Ajou University
- Food & Drug Administration (KFDA), Republic of Korea [10182KFDA992] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Ask authors/readers for more resources
Cytoplasmic I kappa B proteins are primary regulators that interact with NF-kappa B subunits in the cytoplasm of unstimulated cells. Upon stimulation, these IkB proteins are rapidly degraded, thus allowing NF-kB to translocate into the nucleus and activate the transcription of genes encoding various immune mediators. Subsequent to translocation, nuclear IkB proteins play an important role in the regulation of NF-kB transcriptional activity by acting either as activators or inhibitors. To date, molecular basis for the binding of I kappa B alpha, I kappa B beta and I kappa B zeta along with their partners is known; however, the activation and inhibition mechanism of the remaining I kappa B (I kappa BNS, I kappa Be and Bcl-3) proteins remains elusive. Moreover, even though I kappa B proteins are structurally similar, it is difficult to determine the exact specificities of I kappa B proteins towards their respective binding partners. The three-dimensional structures of I kappa BNS, I kappa B zeta and I kappa B epsilon were modeled. Subsequently, we used an explicit solvent method to perform detailed molecular dynamic simulations of these proteins along with their known crystal structures (I kappa B alpha, I kappa B beta and Bcl-3) in order to investigate the flexibility of the ankyrin repeat domains (ARDs). Furthermore, the refined models of IkBNS, IkBe and Bcl-3 were used for multiple protein-protein docking studies for the identification of I kappa BNS-p50/p50, I kappa B epsilon-p50/p65 and Bcl-3-p50/p50 complexes in order to study the structural basis of their activation and inhibition. The docking experiments revealed that I kappa B epsilon masked the nuclear localization signal (NLS) of the p50/p65 subunits, thereby preventing its translocation into the nucleus. For the Bcl-3-and I kappa BNS-p50/p50 complexes, the results show that Bcl-3 mediated transcription through its transactivation domain (TAD) while I kappa BNS inhibited transcription due to its lack of a TAD, which is consistent with biochemical studies. Additionally, the numbers of identified flexible residues were equal in number among all IkB proteins, although they were not conserved. This could be the primary reason for their binding partner specificities.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available