Apoptotic protease-activating factor 1 with ADP
Homo sapiens (human)
Apoptosis is the process of programmed cell death during which a cell kills itself as a result of external or internal stimuli. Apoptosis depends on a family of proteases that need to be activated in order to cleave key proteins in the cell. These proteases are called caspases. Under normal cellular conditions, caspases are present in their inactive form as procaspases. Procaspases need to be cleaved to become active caspases. Active caspases further cleave more procaspases resulting in an amplifying cascade that produces a large amount of active caspases. The activation of caspases is triggered by proteins called adaptor proteins which, in response to a stimulus, bind to initiator procaspases causing their aggregation. Initiator procaspases have some proteolytic activity which is triggered by aggregation resulting in their mutual cleavage and the activation of the caspase cascade. One such adaptor protein is the apoptotic protease-activating factor 1 (Apaf-1). Damaged cells trigger apoptosis from within through the release of the electron carrier, cytochrome c, from the mitochondria into the cytosol. Apaf-1 bound to cytochrome c forms an apoptosome in the presence of ATP/dATP. The apoptosome recruits the initiator caspase, caspase-9, causing its activation and triggering the caspase cascade, leading to apoptosis.
Apaf-1 consists of 3 domains - the N-terminal caspase recruitment domain (CARD), a central nucleotide-binding oligomerization domain (NOD) and a carboxy-terminal domain with multiple WD40 repeats. The structure shown is that of Apaf-1 without the WD-40 repeats and with a bound ADP, showing Apaf-1 in an inactive state. In this state, the CARD domain is packed against the other domains of Apaf-1 occluding the caspase-9 binding site. The ADP molecule is buried in Apaf-1 and acts as an organizing center that binds the various domains together holding Apaf-1 in the inactive state. The binding of ATP to Apaf-1 and its further hydrolysis results in conformational changes required for the formation of the apoptosome and the binding and activation of caspase-9.
Protein Data Bank (PDB)
Riedl, S.J. Li, W. Chao, Y. Schwarzenbacher, R. Shi, Y.; "Structure of the apoptotic protease-activating factor 1 bound to ADP"; Nature; (2005) 434:926-933 PubMed:15829969.
author: Ashwini Patil