BAR: An apoptosis regulator at the intersection of caspases and Bcl-2 family proteins

Two major pathways for induction of apoptosis have been identified-intrinsi c and extrinsic. The extrinsic pathway is represented by tumor necrosis fac tor family receptors, which utilize protein interaction modules known as de ath domains and death effector domains (DEDs) to assemble receptor signalin g complexes that recruit and activate certain caspase-family cell death pro teases, namely procaspases-8 and -10. The intrinsic pathway for apoptosis i nvolves the participation of mitochondria, which release caspase-activating proteins. Bcl-2 family proteins govern this mitochondria-dependent apoptos is pathway, with proteins such as Bar functioning as inducers and proteins such as Bcl-2 and Bcl-X-L serving as suppressors of cell death. An apoptosi s regulator, BAR, was identified by using a yeast-based screen for inhibito rs of Bar-induced cell death. The BAR protein contains a SAM domain, which is required for its interactions with Bcl-2 and Bcl-X-L and for suppression of Bar-induced cell death in both mammalian cells and yeast. In addition, BAR contains a DED-like domain responsible for its interaction with DED-con taining procaspases and suppression of Fas-induced apoptosis, Furthermore, BAR can bridge procaspase-8 and Bcl-2 into a protein complex. The BAR prote in is anchored in intracellular membranes where Bcl-2 resides. BAR therefor e may represent a scaffold protein capable of bridging two major apoptosis pathways.