Molecular docking analysis of the protein-protein interaction between RelA-associated inhibitor and tumor suppressor protein p53 and its inhibitory effect on p53 action.
RelA-associated inhibitor (RAI) was initially identified as a protein that interacts with the p65 subunit (RelA) of nuclear factor-kappaB. It was recently found to interact with the p53 tumor suppressor protein. RAI is a structural homolog of the p53-binding protein 2 and I kappaB family proteins, and is known to inhibit the DNA-binding activities of p65 and p53. In the present study, we have attempted to predict the 3-dimensional structure of RAI in complex with p53 using computational chemistry. In order to evaluate the predicted structure model, we created a series of RAI mutants in which the amino acid residues involved in the interaction with p53 were mutated, and examined their activities in blocking p53-mediated bax gene expression. Our observations support the validity of the predicted 3-dimensional model of the p53-RAI protein complex. Based on the p53-RAI complex model, we have demonstrated the biological importance of the R248 and R273 residues of p53, and the D775 and E795 residues of RAI, in the protein-protein interaction between p53 and RAI and the biological actions of these proteins. These findings will further clarify the biological actions of RAI in carcinogenesis and can be used for the development of a novel strategy in blocking the actions of RAI. The possible biological implications of RAI are also discussed.
Tomoda
Keisuke
K
Department of Molecular and Cellular Biology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
Takahashi
Naoko
N
Hibi
Yurina
Y
Asamitsu
Kaori
K
Ishida
Hirokazu
H
Kondo
Toshiharu
T
Fujii
Yoshitaka
Y
Okamoto
Takashi
T
D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011487:Protein Conformation; D012097:Repressor Proteins; D051996:Transcription Factor RelA / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; C119612:PPP1R13L protein, human; D012097:Repressor Proteins; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53