title: Mapping the interaction of pro-apoptotic tBID with pro-survival BCL-XL.
abstract: 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.
authors: Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
authors: Yong
authors: Y
authors: Yao
authors: Andrey A
authors: AA
authors: Bobkov
authors: Leigh A
authors: LA
authors: Plesniak
authors: Francesca M
authors: FM
authors: Marassi
mesh_terms: D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry* / Q000378:metabolism* / Q000502:physiology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000737:chemistry* / Q000378:metabolism* / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D019281:Dimerization; D019277:Entropy; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000502:physiology; D051020:bcl-X Protein / Q000737:chemistry* / Q000378:metabolism* / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D051020:bcl-X Protein