Mapping the Interaction of Pro-Apoptotic tBID with Pro-Survival BCL-XL

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• 作者：Yong Yao ; Andrey A. Bobkov ; Leigh A. Plesniak ; Francesca M. Marassi
• 刊名：Biochemistry
• 出版年：2009
• 出版时间：September 15, 2009
• 年：2009
• 卷：48
• 期：36
• 页码：8704-8711
• 全文大小：1064K
• 年卷期：v.48,no.36(September 15, 2009)
• ISSN：1520-4995

文摘

The BH3-only BCL-2 family protein BID is activated by caspase-8 cleavage upon engagement of cell surface death receptors. The resulting 15 kDa C-terminal fragment, tBID, translocates to mitochondria, triggering the release of cytotoxic molecules and cell death. The pro-apoptotic activity of tBID is regulated by its interactions with pro-survival BCL-XL and pro-death BAX, both in the cytosol and at the mitochondrial membrane. In this study, we characterize the molecular interactions between full-length tBID and BCL-XL using NMR spectroscopy and isothermal titration calorimetry (ITC). In aqueous solution, tBID adopts an α-helical but dynamically disordered conformation; however, the three-dimensional conformation is stabilized when tBID engages its BH3 domain in the BH3-binding hydrophobic groove of BCL-XL to form a stable heterodimeric complex. Characterization of the binding thermodynamics by ITC reveals that the interaction between tBID and BCL-XL is driven by enthalpy but disfavored by the entropy associated with the conformational order induced in tBID upon binding BCL-XL.