Using genomic data observed in today's living species, we recently reported an extensive phylogenomic analysis of Bcl-2-related sequences (Aouacheria et al. Mol Biol Evol, 2005). A total of 758 Bcl-2 family genes encoding 896 proteins can currently be accessed in these pages. In addition, various clickable links offer information from other web sites (NCBI, Ensembl, GO, Interpro, etc). At the moment, the database mostly contains information for multidomain Bcl-2 family members (plus Bid). Sequences of BH3-only and viral Bcl-2 family members are currently being added.

In metazoans, the mitochondrial pathway of apoptosis depends on orchestrated interactions between "multidomain" members of the Bcl-2 family. Proteins belonging to this family are either pro- or anti-apoptotic members and govern mitochondrial outer membrane permeabilization, a "point of no return" in programmed cell death.

Although Bcl-2 proteins are long recognized as targets for drug-discovery to treat apoptosis-related human pathologies (from cancer to neurodegenerative diseases), their precise mechanism of action is still to be discovered.

Insights into the mechanisms of Bcl-2 family protein action have emerged from several systems: genetics in Caenorhabditis elegans; biochemistry in cell culture and knockout studies in mice. Over the years, several models for Bcl-2 function have been developed, which are discussed in many reviews. As currently understood, death inducers (e.g. Bax, Bak, BH3-only proteins) promote cytochrome c release from mitochondria, leading to the activation of intracellular cysteine proteases termed caspases. Conversely, pro-survival members such as Bcl-2 or Bcl-xL decrease cell susceptibility to apoptosis by preventing the activation of Bax-like or BH3-only proteins.

At the level of primary structure, prosurvival "multidomain" members generally share sequence similarity in four conserved Bcl-2 homology (BH) domains (BH1-4), while pro-death "multidomain" members contain only two or three BH domains (BH1-3). To date, the human repertoire of multidomain proteins comprises seven prosurvival members (Bcl-2, Bcl-xL, Bcl-w, Mcl-1, Bcl2l10, Bfl-1 and Bcl2l12), and up to six pro-apoptotic members (Bax, Bak, Bok, Bcl-G, Bcl-rambo and Bfk). Over the course of evolution, a number of viruses have captured and modified the structure and the function of cellular Bcl-2 homologues. Interestingly, some of the viral proteins (e.g. A52, K7) adopt a Bcl-2-like fold despite sharing no significant sequence similarity with their cellular counterparts. A last group of death proteins termed the "BH3-only" subfamily (including Bid, Bad, Bik, Bim, Bmf, Noxa, Puma, Hrk, Beclin1 and MULE in humans) exhibits sequence similarity only in the BH3 domain.

Incidentally, the difference between pro(Yin)- and anti(Yang)-apoptotic members is not so much a stable dichotomy. Some findings support the notion that certain Bcl-2 family members are bi-functional, depending on changes in the expression level, alternative splicing and post-translational modifications. Thus, multidomain Bcl-2 proteins are like the Yin and Yang in Taiji, an ancient Chinese philosophy.