How Apaf‐1 relays the death signal in the mitochondrial pathway of apoptosis

Abstract

The apoptotic protease‐activating factor 1 (Apaf‐1) is the key switch in the mitochondrial pathway of apoptosis. Apaf‐1 oligomerizes upon binding of mitochondrially released cytochrome c into the heptameric apoptosome complex, which ignites the downstream cascade of caspases. We have recently solved the 3.0 Å 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‐EM derived model of Apaf‐1 in its apoptosomal conformation, we depict the molecular events that transform Apaf‐1 from auto‐inhibited monomer to a building block of the caspase‐activating apoptosome. Combining the results from X‐ray crystallography, mutational studies, and small angle scattering experiments we elucidate the role of nucleotide exchange for the release of the autoinhibition of Apaf‐1.