The MDM2-binding region in the transactivation domain of p53 also acts as a Bcl-XL-binding motif

• Main Authors: Xu, Huibin, Ye, Hong, Osman, Nur Eliza, Sadler, Kristen, Won, Eun-Young, Chi, Seung-Wook, Yoon, Ho Sup
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2012
• Subjects: DRNTU::Science::Biological sciences::Biochemistry
• Online Access: https://hdl.handle.net/10356/93855; http://hdl.handle.net/10220/7476
• Institution: Nanyang Technological University

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-XL interact with p53 and induce apoptosis. Initially, the p53 DNA-binding domain (p53DBD) was found to bind to Bcl-2 and Bcl-XL. 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-XL. Here, we further document that the transactivation domain of p53 (p53TAD) in p53NTD alone binds to Bcl-XL. We demonstrated that the MDM2-binding region (residues S15 to N29, herein referred to as SN15) in p53TAD is the binding site for Bcl-XL. The binding interface on Bcl-XL 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-XL 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-XL. A Bcl-XL/SN15 complex structural model suggests that the SN15 peptide adopts an extended α-helical structure to bind to the hydrophobic pocket on the Bcl-XL, which is similar to the mode of binding between BH3 peptides and Bcl-XL.