APAF1
APAF1 (apoptotic protease-activating factor 1) is the cytosolic scaffold that assembles the apoptosome, the heptameric complex that activates caspase-9.
Function
When the mitochondrial outer membrane permeabilizes, cytochrome c escapes into the cytosol and binds APAF1. The binding, together with dATP, converts APAF1 from a folded-inactive monomer into an open form that oligomerizes into a seven-spoked wheel - the apoptosome. Each spoke presents a caspase recruitment domain that captures procaspase-9, dimerizes it, and thereby activates it; active caspase-9 then cleaves executioner caspases (caspase-3) and the cell dismantles itself. APAF1 activation is therefore the step at which mitochondrial outer-membrane permeabilization commits the cell to caspase-dependent death.
In cancer
p53 induces APAF1 transcription as part of the apoptotic response to DNA damage. Loss of APAF1 expression - through methylation of its promoter or through mutation - occurs in melanoma and other tumors and blunts the apoptotic response of a cell whose damage checkpoints are otherwise intact. A cell with intact checkpoints and a broken apoptosome arrests instead of dying, which changes how the tumor evolves.
Notes
- Human gene symbol: APAF1; UniProt O14727; 1,248 amino acids; CARD, NB-ARC (nucleotide-binding), and WD40 repeat domains.