The proapoptotic protein Bad binds the amphipathic groove of 14-3-3ζ

• Published in: Biochimica et biophysica acta, Protein structure and molecular enzymology Protein structure and molecular enzymology, 2001-06, Vol.1547 (2), p.313-319
• Main Authors: Yang, Hongzhu, Masters, Shane C., Wang, Haining, Fu, Haian
• Format: Article
• Language: English
• Subjects: 14-3-3; Apoptosis; Bad
• ISSN: 0167-4838; 1879-2588
• DOI: 10.1016/S0167-4838(01)00202-3

Through interaction with a multitude of target proteins, 14-3-3 proteins participate in the regulation of diverse cellular processes including apoptosis. These 14-3-3-interacting proteins include a proapoptotic Bcl-2 homolog, Bad (Bcl-2/Bcl-XL-associated death promoter). To understand how 14-3-3 interacts with Bad and modulates its function, we have identified structural elements of 14-3-3 necessary for 14-3-3/Bad association. 14-3-3 contains a conserved amphipathic groove that is required for binding to several of its ligands. We used peptides of known binding specificity as competitors to demonstrate that Bad interacts with 14-3-3ζ via its amphipathic groove. More detailed analysis revealed that several conserved residues in the groove, including Lys-49, Val-176, and Leu-220, were critical for Bad interaction. These results were applied to investigations of the ability of 14-3-3 to prevent Bad-induced cell death. When co-expressed with Akt, wild-type 14-3-3 could reduce the ability of Bad to cause death, however 14-3-3ζK49E, which cannot bind Bad, failed to inhibit Bad. It seems that the amphipathic groove of 14-3-3 represents a general binding site for multiple ligands, raising issues related to competition of ligands for 14-3-3.