National Center for
3SFZ: Crystal Structure Of Full-Length Murine Apaf-1
Crystal structure of full-length apaf-1: how the death signal is relayed in the mitochondrial pathway of apoptosis
Structure (2011) 19 p.1074-1083
The apoptotic protease-activating factor 1 (Apaf-1) relays the death signal in the mitochondrial pathway of apoptosis. Apaf-1 oligomerizes on binding of mitochondrially released cytochrome c into the heptameric apoptosome complex to ignite the downstream cascade of caspases. Here, we present the 3.0 A crystal structure of full-length murine Apaf-1 in the absence of cytochrome c. The structure shows how the mammalian death switch is kept in its "off" position. By comparing the off state with a recent cryo-electron microscopy derived model of Apaf-1 in its apoptosomal conformation, we depict the molecular events that transform Apaf-1 from autoinhibited monomer to a building block of the caspase-activating apoptosome. Moreover, we have solved the crystal structure of the R265S mutant of full-length murine Apaf-1 in the absence of cytochrome c to 3.55 A resolution and we show that proper function of Apaf-1 relies on R265 in the vicinity of the bound nucleotide.