Defining the p53 DNA‐binding domain/Bcl‐xL‐binding interface using NMR

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Abstract
P53 exerts its tumor suppressor activity through both transcription‐dependent and transcription‐independent processes. Although the transcription‐dependent activity of p53 has been extensively studied, the mechanism for transcription‐independent p53‐mediated tumor suppression is less well known. Recently, it was reported that p53 can directly induce mitochondrial permeabilization and promote apoptosis. This occurs through complexation of the DNA‐binding region of p53 with the anti‐apoptotic proteins Bcl‐xL and Bcl‐2 (Mihara, M. et al. (2003) Mol. Cell 11, 577–590). Using nuclear magnetic resonance (NMR) spectroscopy we show that the interaction surface on p53 involves the same region that is used by the protein to contact DNA. The p53‐binding site on Bcl‐xL consists of the carboxy‐terminus of the first α‐helix, the loop between α3 and α4, and the loop between α5 and α6 of Bcl‐xL. Furthermore, the interaction of p53 with Bcl‐xL is blocked by the binding of a 25‐residue peptide derived from the BH3 region of the pro‐apoptotic protein referred to as Bad.