The MDM2-Binding Region in the Transactivation Domain of p53 Also Acts as a Bcl-XL-Binding Motif

While the transcription-dependent mechanism of p53 has been extensively studied, recently the transcription-independent apoptotic activity of p53 has also been described. Bcl-2 and Bcl-X-L interact with p53 and induce apoptosis. Initially, the p53 DNA-binding domain (p53DBD) was found to bind to Bcl-2 and Bcl-X-L. Later, the p53 N-terminal domain (p53NTD) was reported to be sufficient for inducing the transcription-independent apoptotic activity of p53 and also shown to interact with Bcl-X-L. Here, we further document that the transactivation domain of p53 (p53TAD) in p53NTD alone binds to Bcl-X-L. We demonstrated that the MDM2-binding region (residues S15 to N29, herein referred to as SN15) in p53TAD is the binding site for Bcl-X-L. The binding interface oil Bcl-X-L was identified at the hydrophobic pocket formed by the BH1, BH2, and BH3 domains, which also binds to the Bak/Bad BH3 peptides, suggesting Bcl-X-L and MDM2 share a common binding motif in p53TAD. Our NMR structural studies have shown that the SN15 peptide undergoes a conformational change upon binding to Bcl-X-L. A Bcl-X-L/SN15 complex structural model suggests that the SN15 peptide adopts an extended alpha-helical Structure to bind to the hydrophobic pocket on the Bcl-X-L, which is similar to the mode of binding between BH3 peptides and Bcl-X-L.