1. Bcl-2 subfamily (pro-survival): Bcl-2, Bcl-XL, Bcl-w, Mcl-1 and A1;
2. Bax subfamily (pro-apoptotic): Bax, Bak and Bok;
3. BH3 subfamily (pro-apoptotic): Bad, Bid, Bik, Blk, Hrk, BNIP3 and BimL;
Additionally, several Bcl-2 homologs have been identified in viruses, among others the adenovirus oncoprotein E1B-19K.
The bcl-2 gene codes for a 25 kDa protein. The C terminal 21 amino acids encode a stretch of hydrophobic amino acids that are important in membrane docking: Bcl-2 resides on the cytoplasmic face of the mitochondrial outer membrane, the nuclear envelop, and the endoplasmic reticulum. Deletion of the C terminus does not abrogate Bcl-2 survival function! Most Bcl-2 homologs have this hydrophobic C terminal domain, though they not necessarily are located on membranes but are cytosolic (e.g. Bax).
When homologs of Bcl-2 have been identified, it became apparent that the Bcl-2 family can be defined by the presence of conserved motifs known as Bcl-2 homology domains (BH1 to BH4). While Bcl-2 and its most similar prosurvival homologs Bcl-XL and Bcl-w contain all four BH domains, the other pro-survival members contain at least BH1 and BH2. While the members of the Bax subfamily contain BH1, BH2 and BH3, and resemble Bcl-2 fairly closely, the seven mammalian members of the BH3 subfamily possess only the central short (9 - 16 residue) BH3 domain and are unrelated to any known protein. The BH3 subfamily members may well represent the physiological antagonists of the pro-survival proteins, since programmed cell death in C. elegans requires EGL-1 (the one non-mammalian BH3 family member) and Bid was reported to link caspase-8 activity to cytochrome c release.
Pro- and anti-apoptotic family members can heterodimerize: the BH1, BH2 and BH3 domains of an anti-apoptotic member (e.g. Bcl-XL) form a hydrophobic cleft to which a BH3 amphipathic alpha-helix can bind (Sattler et al., 1997, Science, 275: 983). This BH3 cleft coupling, reminiscent of ligand-receptor engagement, may account for all dimerization within the family. Heterodimerization is not required for pro-survival function (contrary to early indications) but is essential for the pro-apoptotic activity in the BH3 subfamily. The Bax subfamily members do not depend essentially on heterodimerization, but possibly have an independent cytotoxic impact.
Bcl-2 family members regulate Cytochrome c release
The pro-survival proteins also seem to maintain organelle integrity since Bcl-2 directly or indirectly prevents the release of cytochrome c from mitochondria (Yang et al, 1997, Science, 275: 1129-1132). On the other hand, the pro-apoptotic BH3 subfamily member BID was reported to mediate the release of cytochrome c (without evoking mitochondrial swelling and permeability transition). Interestingly, BID is able to bind to pro-apoptotic members of the Bcl-2 family (e.g. Bax) as well as to pro-survival members Bcl-2 and Bcl-XL (Luo et al., 1998, Cell, 94: 481-490).
Bax maybe involved in Caspase-Independent Death
The BH1 and BH2 domains of Bcl-2 family members (Bcl-2, Bcl-XL and Bax) resemble membrane insertion domains of bacterial toxins: hypothetically they can form pores in organelles such as mitochondria, what at least was demonstrated in lipid bilayers in vitro. In yeast - which lack Bcl-2 like proteins, CED-4 and caspases - Bax and Bak were shown to induce cell death, while Bcl-2 can protect, apparently by preventing mitochondrial disruption (Green and Reed, 1998, Science, 281: 1309). Bax and Bax-like proteins might mediate caspase-independent death via channel-forming activity, which would promote the mitochondrial