Bcl-2 proteins and mitochondria-Specificity in membrane targeting for death

► This review highlights the various mechanisms that target Bcl-2 proteins to mitochondria. ► Multi-domain Bcl-2 proteins target to mitochondria via their C-terminal tail anchor. ► How membrane specificity is achieved for tail anchor containing Bcl-2 proteins is unclear, and may require interactions with other mitochondrial proteins. ► The mechanisms targeting BH3-only proteins to mitochondria are distinct from those used by the multi-domain proteins. ► Targeting of BH3 proteins involves both protein-lipid and protein-protein interactions on the OMM.