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http://dx.doi.org/10.14348/molcells.2014.0001

A Conserved Mechanism for Binding of p53 DNA-Binding Domain and Anti-Apoptotic Bcl-2 Family Proteins  

Lee, Dong-Hwa (Medical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology)
Ha, Ji-Hyang (Medical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology)
Kim, Yul (Department of Bio and Brain Engineering, Korea Advanced Institute for Science and Technology)
Jang, Mi (Medical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology)
Park, Sung Jean (College of Pharmacy, Gachon University)
Yoon, Ho Sup (Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University)
Kim, Eun-Hee (Division of Magnetic Resonance, Korea Basic Science Institute)
Bae, Kwang-Hee (Research Center for Integrated Cellulomics, Korea Research Institute of Bioscience and Biotechnology)
Park, Byoung Chul (Medical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology)
Park, Sung Goo (Medical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology)
Yi, Gwan-Su (Department of Bio and Brain Engineering, Korea Advanced Institute for Science and Technology)
Chi, Seung-Wook (Medical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology)
Publication Information
Molecules and Cells / v.37, no.3, 2014 , pp. 264-269 More about this Journal
Abstract
The molecular interaction between tumor suppressor p53 and the anti-apoptotic Bcl-2 family proteins plays an essential role in the transcription-independent apoptotic pathway of p53. In this study, we investigated the binding of p53 DNA-binding domain (p53DBD) with the anti-apoptotic Bcl-2 family proteins, Bcl-w, Mcl-1, and Bcl-2, using GST pull-down assay and NMR spectroscopy. The GST pull-down assays and NMR experiments demonstrated the direct binding of the p53DBD with Bcl-w, Mcl-1, and Bcl-2. Further, NMR chemical shift perturbation data showed that Bcl-w and Mcl-1 bind to the positively charged DNA-binding surface of p53DBD. Noticeably, the refined structural models of the complexes between p53DBD and Bcl-w, Mcl-1, and Bcl-2 showed that the binding mode of p53DBD is highly conserved among the anti-apoptotic Bcl-2 family proteins. Furthermore, the chemical shift perturbations on Bcl-w, Mcl-1, and Bcl-2 induced by p53DBD binding occurred not only at the p53DBD-binding acidic region but also at the BH3 peptide-binding pocket, which suggests an allosteric conformational change similar to that observed in Bcl-$X_L$. Taken altogether, our results revealed a structural basis for a conserved binding mechanism between p53DBD and the anti-apoptotic Bcl-2 family proteins, which shed light on to the molecular understanding of the transcription-independent apoptosis pathway of p53.
Keywords
apoptosis; Bcl-2 family proteins; binding mechanism; DNA-binding domain; p53;
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