Mapping the interaction of pro-apoptotic tBID with pro-survival BCL-XL

Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
Biochemistry (Impact Factor: 3.02). 09/2009; 48(36):8704-11. DOI: 10.1021/bi901171n
Source: PubMed


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 alpha-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.

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    • "The conserved aspartic acid, D, forms a salt bridge with a conserved arginine in the BH1 motif of the pro-survival protein. Analysis of Bim and tBid binding to Bcl-w [21] and Bcl-xL [25] show that helical structure is only induced over the BH3 motif and outside this region the sequence remains poorly ordered. "
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