Apoptosis is a very important cellular process in which mitochondria play a crucial role. During apoptosis, mitochondrial outer membrane (MOM) becomes permeabilized and releases many apoptotic factors (including cytochrome c and SMAC) from the mitochondrial intermembrane space into cytosol. This process is known to be regulated by Bcl-2 family proteins. Particularly, the multidomain pro-apoptotic Bcl-2 family proteins Bax and Bak are mainly responsible for forming pores at MOM. The anti-apoptotic Bcl-2 family proteins (including Bcl-2, Mcl-1 and Bcl-xL), on the other hand, can inhibit this process. Interestingly, although these two groups of proteins perform opposite apoptotic functions, their structures are very similar....[ Read more ]

Apoptosis is a very important cellular process in which mitochondria play a crucial role. During apoptosis, mitochondrial outer membrane (MOM) becomes permeabilized and releases many apoptotic factors (including cytochrome c and SMAC) from the mitochondrial intermembrane space into cytosol. This process is known to be regulated by Bcl-2 family proteins. Particularly, the multidomain pro-apoptotic Bcl-2 family proteins Bax and Bak are mainly responsible for forming pores at MOM. The anti-apoptotic Bcl-2 family proteins (including Bcl-2, Mcl-1 and Bcl-xL), on the other hand, can inhibit this process. Interestingly, although these two groups of proteins perform opposite apoptotic functions, their structures are very similar.

In this study, we investigated the molecular apoptotic mechanisms of Bcl-2 family proteins by asking the following questions: (1) Why do these structurally similar proteins play opposite roles? (2) What are the roles of different functional domains in determining the apoptotic properties? Also, using Bcl-xL as an example, we studied the detailed roles played by anti-apoptotic Bcl-2 family proteins in regulating apoptosis.

We used a combination of molecular, biochemical and living cell imaging techniques in this study. Our major findings are: (1) All of the Bcl-2 family proteins appear to possess an intrinsic pro-apoptotic activity. (2) The N-terminus is an inhibitory domain for this intrinsic property. (3) In the absence of N-terminus, the apoptotic potency is mainly determined by membrane affinity of the alpha 5/6 domains. (4) Charge distribution in the alpha 5/6 domains is also important. Finally, using Bcl-xL as an example, we demonstrated that anti-apoptotic proteins play multiple roles in regulating apoptosis. This study is aimed to provide an in-depth understanding on how the Bcl-2 family proteins regulate apoptosis. Our findings may facilitate the design of small molecular inhibitors of Bcl-2 family proteins, which could serve as potential drugs for apoptosis-related diseases, such as cancers and Alzheimer’s disease.