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Ha, Ji-Hyang,Shin, Jae-Sun,Yoon, Mi-Kyung,Lee, Min-Sung,He, Fahu,Bae, Kwang-Hee,Yoon, Ho Sup,Lee, Chong-Kil,Park, Sung Goo,Muto, Yutaka,Chi, Seung-Wook American Society for Biochemistry and Molecular Bi 2013 The Journal of biological chemistry Vol.288 No.10
<P>Molecular interactions between the tumor suppressor p53 and the anti-apoptotic Bcl-2 family proteins play an important role in the transcription-independent apoptosis of p53. The p53 transactivation domain (p53TAD) contains two conserved Φ<I>XX</I>ΦΦ motifs (Φ indicates a bulky hydrophobic residue and <I>X</I> is any other residue) referred to as p53TAD1 (residues 15–29) and p53TAD2 (residues 39–57). We previously showed that p53TAD1 can act as a binding motif for anti-apoptotic Bcl-2 family proteins. In this study, we have identified p53TAD2 as a binding motif for anti-apoptotic Bcl-2 family proteins by using NMR spectroscopy, and we calculated the structures of Bcl-X<SUB>L</SUB>/Bcl-2 in complex with the p53TAD2 peptide. NMR chemical shift perturbation data showed that p53TAD2 peptide binds to diverse members of the anti-apoptotic Bcl-2 family independently of p53TAD1, and the binding between p53TAD2 and p53TAD1 to Bcl-X<SUB>L</SUB> is competitive. Refined structural models of the Bcl-X<SUB>L</SUB>·p53TAD2 and Bcl-2·p53TAD2 complexes showed that the binding sites occupied by p53TAD2 in Bcl-X<SUB>L</SUB> and Bcl-2 overlap well with those occupied by pro-apoptotic BH3 peptides. Taken together with the mutagenesis, isothermal titration calorimetry, and paramagnetic relaxation enhancement data, our structural comparisons provided the structural basis of p53TAD2-mediated interaction with the anti-apoptotic proteins, revealing that Bcl-X<SUB>L</SUB>/Bcl-2, MDM2, and cAMP-response element-binding protein-binding protein/p300 share highly similar modes of binding to the dual p53TAD motifs, p53TAD1 and p53TAD2. In conclusion, our results suggest that the dual-site interaction of p53TAD is a highly conserved mechanism underlying target protein binding in the transcription-dependent and transcription-independent apoptotic pathways of p53.</P>