期刊
NATURE CHEMICAL BIOLOGY
卷 9, 期 3, 页码 163-168出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1166
关键词
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资金
- US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]
- NIH [R01CA082491, 1R01GM083159, R01GM52735, R01GM96208, R01 CA157740]
- JJR Foundation
- William A. Spivak Fund
- Fridolin Charitable Trust
- National Cancer Institute Cancer Center [P30CA21765]
- March of Dimes Foundation [5-FY11-74]
- American Lebanese Syrian Associated Charities
- University of Tennessee Health Sciences Center
Following DNA damage, nuclear p53 induces the expression of PUMA, a BH3-only protein that binds and inhibits the antiapoptotic BCL-2 repertoire, including BCL-xL. PUMA, unique among BH3-only proteins, disrupts the interaction between cytosolic p53 and BCL-xL, allowing p53 to promote apoptosis via direct activation of the BCL-2 effector molecules BAX and BAK. Structural investigations using NMR spectroscopy and X-ray crystallography revealed that PUMA binding induced partial unfolding of two alpha-helices within BCL-xL. Wild-type PUMA or a PUMA mutant incapable of causing binding-induced unfolding of BCL-xL equivalently inhibited the antiapoptotic BCL-2 repertoire to sensitize for death receptor-activated apoptosis, but only wild-type PUMA promoted p53-dependent, DNA damage-induced apoptosis. Our data suggest that PUMA-induced partial unfolding of BCL-xL disrupts interactions between cytosolic p53 and BCL-xL, releasing the bound p53 to initiate apoptosis. We propose that regulated unfolding of BCL-xL provides a mechanism to promote PUMA-dependent signaling within the apoptotic pathways.
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