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

作者：Lee Dong Hwa; Ha Ji Hyang; Kim Yul; Jang Mi; Park Sung Jean; Yoon Ho Sup; Kim Eun Hee; Bae Kwang Hee; Park Byoung Chul; Park Sung Goo; Yi Gwan Su^*; Chi Seung Wook

来源：Molecules and Cells, 2014, 37(3): 264-269.

DOI：10.14348/molcells.2014.0001

• apoptosis
• Bcl-2 family proteins
• binding mechanism
• DNA-binding domain
• p53

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-XL. 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.

• 出版日期2014-3-31
• 单位南阳理工学院