The MDM2-binding region in the transactivation domain of p53 also acts as a Bcl-X(L)-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 on 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).
Xu
Huibin
H
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
Ye
Hong
H
Osman
Nur Eliza
NE
Sadler
Kristen
K
Won
Eun-Young
EY
Chi
Seung-Wook
SW
Yoon
Ho Sup
HS
D020816:Amino Acid Motifs; D001665:Binding Sites; D006801:Humans; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D051736:Proto-Oncogene Proteins c-mdm2