Anti-apoptosis Proteins Mcl-1 and Bcl-xL Have Different p53-Binding Profiles
- 影响因子：
0.0
- DOI码：
10.1021/bi400690m
- 发表刊物：
Biochemistry
- 摘要：
One of the transcription-independent mechanisms of the tumor suppressor p53 discovered in recent years involves physical interaction between p53 and proteins of the Bcl-2 family. In this paper, significant differences between the interaction of p53 with Mcl-1 and Bcl-xL were demonstrated by NMR spectroscopy and isothermal titration calorimetry. Bcl-xL was found to bind strongly to the p53 DNA-binding domain (DBD) with a dissociation constant (Kd) of ~600 nM, whereas Mcl-1 binds to the p53 DBD weakly with a dissociation constant in the mM range. In contrast, the p53 transactivation domain (TAD) binds weakly to Bcl-xL with a Kd ~ 300-500 μM and strongly to Mcl-1 with a Kd ~ 10-20 μM. NMR titrations indicate that although the p53 TAD binds to the BH3-binding grooves of both Bcl-xL and Mcl-1, Bcl-xL prefers to bind to the first subdomain (TAD1) in the p53 TAD, and Mcl-1 prefers to bind to the second subdomain (TAD2). Therefore, Mcl-1 and Bcl-xL have different p53-binding profiles. This indicates that the detailed interaction mechanisms are different, although both Mcl-1 and Bcl-xL can mediate transcription-independent cytosolic roles of p53. The revealed differences in binding sites and binding affinities should be considered when BH3 mimetics are used in cancer therapy development.
- 论文编号：
42
- 卷号：
52(37)
- 页面范围：
6324-34
- 是否译文：
否
- 发表时间：
2013-01-01
- 发布期刊链接：
- 第一作者：
Yao H
- 通讯作者：
Feng Y,Xia Bin
- 全部作者：
Wang J,Perrett S,Xu N,Lin J,Gong W,Mi S
