Anti-apoptosis Proteins Mcl-1 and Bcl-xL Have Different p53-Binding Profiles

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• 作者：Hongwei Yao ; Shuofu Mi ; Weibin Gong ; Jian Lin ; Nuo Xu ; Sarah Perrett ; Bin Xia ; Jinfeng Wang ; Yingang Feng
• 刊名：Biochemistry
• 出版年：2013
• 出版时间：September 17, 2013
• 年：2013
• 卷：52
• 期：37
• 页码：6324-6334
• 全文大小：800K
• 年卷期：v.52,no.37(September 17, 2013)
• ISSN：1520-4995

文摘

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 (K_d) 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 K_d 300鈥?00 渭M and strongly to Mcl-1 with a K_d 10鈥?0 渭M. 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.