Journal
BIOCHEMISTRY
Volume 52, Issue 37, Pages 6324-6334Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi400690m
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Funding
- National Natural Science Foundation of China [30800179, 30970571, 30170201, 30770434]
- 973 Program of China [2012CB910700]
- Beijing Natural Science Foundation [5092018]
- China Postdoctoral Science Foundation [20090460350]
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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 similar to 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 similar to 300-500 mu M and strongly to Mcl-1 with a K-d similar to 10-20 mu 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.
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