BAK multimerization for apoptosis, but not bid binding, is inhibited by negatively charged residue in the BAK hydrophobic groove

Molecular Cancer

Short Communication

Alan Storey¹  Abul Azad¹ 

[1] Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS, Oxford, UK;

关键词: Apoptosis;    Mitochondria;    BCL-2;    BAK;    BH3;    c;    Tyrosine Phosphorylation;    DNA damage;   

DOI  :  10.1186/1476-4598-12-65

 received in 2013-01-24, accepted in 2013-06-05,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundBCL-2 family proteins BAK and BAX orchestrate outer mitochondrial membrane permeabilization (MOMP) during apoptosis by forming pores in the membrane to release apoptogenic factors that commits a cell to death. BAK and BAX therefore function as a ‘point of no return’ in the apoptotic cascade. BAK activation is a multi-step process involving conformational changes, mediated by BH3-only proteins or p53, which lead eventually to oligomerization and pore formation. Further, recent reports show that BAK activation is also linked to and dependent upon dephosphorylation of both tyrosine and serine residues.FindingsWe hypothesized that phosphorylation of BAK at tyrosine residue 110 (Y110) was functionally important during the BAK activation process. BAK/BAX double knockout HCT116 cells expressing a phosphor-mimetic BAK mutant (BAK Y110E), showed impaired dimerization and multimerization capacity when treated with either UV irradiation or etoposide when compared to cells reconstituted to express wild-type BAK. The Y110E mutant also showed decreased release of cytochrome c from isolated mitochondria challenged with tBid protein, resulting in a failure to activate caspase 3. Interestingly, co-immunoprecipitation experiments suggest that a negative charge at this residue may be important for the recruitment of Bid to BAK, but conversely that this also impairs BAK:BAK interactions.ConclusionThese findings implicate dephosphorylation of Y110 as having an important mechanistic role in BAK activation, and underscores how post-translational modifications are intimately linked and coupled to the protein-protein interactions required for BAK activation during apoptosis.

【 授权许可】

CC BY   
© Azad and Storey; licensee BioMed Central Ltd. 2013