APAF-1 Signaling

Abstract

APAF-1 was identified in 1997 as a homolog of C. elegans cell death 4 (CED-4) gene. APAF-1 is a cytoplasmatic protein of 1194 aminoacids able to bind cytochrome-c and contributing to ▶caspase-9 activation. APAF-1 protein exists in cells in an inactive monomeric form. Signals that activate the intrinsic pathway of apoptosis (such as developmental cues, genomic stress, endoplasmic reticulum stress, cytotoxic damage, ▶hypoxia, growth factor deprivation, and cell detachment) lead to ▶mitochondria outer membrane permeabilization (MOMP). As a result of MOMP, cytochrome-c, a component of the mitochondrial respiratory chain, present in the intermembrane space, is released from mitochondria into the cytosol, where it binds to APAF-1. Upon binding of cytochrome-c, in the presence of dATP/ATP, APAF-1 undergoes a conformational change. This triggers APAF-1 oligomerization into a heptameric complex named apoptosome. The APAF-1-cytochrome-c apoptosome is a wheel–like multiprotein particle with seven spokes and a central hub that is able to recruit and activate the initiator caspase-9. In turn, caspase-9 activates other effector caspases, such as caspase-3 and caspase-7, which execute the cell death program.