CYCS binds to APAF1

Stable Identifier
Homo sapiens
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The apoptotic protease‑activating factor 1 (APAF1) is a cytosolic multidomain adapter protein containing an N‑terminal caspase recruitment domain (CARD), followed by a central nucleotide‑binding & oligomerization domain (NOD, also known as NB‑ARC) and a C‑terminal regulatory region with WD40 repeats which form the 7- and 8-bladed β-propellers (Inohara N and Nunez G 2003; Danot O et al. 2009; Yuan S et al. 2011). Under steady‑state, non‑apoptotic conditions, APAF1 exists as an ADP‑bound, autoinhibited monomer (Riedl SJ et al. 2005; Reubold TF et al. 2009). During apoptosis, cytochrome c (CYCS) is released from the mitochondrial intermembrane space to the cytosol where it binds APAF1 between the two WD40 repeat domains in the C‑terminal regulatory region (Zou et al. 1997; Liu X et al. 1996; Shalaeva DN et al. 2015; Zhou M et al. 2015). CYCS binding causes an upward rotation of the β-propeller region which is accompanied by conformational changes in APAF1 and the replacement of ADP by dATP or ATP triggering APAF1 oligomerization into a heptameric, wheel‑shaped signaling platform (Acehan D et al. 2002; Yu X et al. 2005, Kim HE et al. 2005; Yuan S et al. 2010, 2013; Li P et al. 1997; Jiang X & Wang X 2000; Zhou M et al. 2015). Moreover, the N-terminal CARD in the inactive APAF1 monomer is not shielded from other proteins by β–propellers. Hence, the APAF1 CARD may be free to interact with a procaspase-9 CARD either before or during apoptosome assembly (Yuan S et al. 2013). Physiological concentrations of calcium ion negatively affect the assembly of apoptosome and activation of CASP9 by inhibiting nucleotide exchange in the monomeric, autoinhibited APAF1 (Bao Q et al. 2007).

Literature References
PubMed ID Title Journal Year
9267021 Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3

Wang, X, Henzel, WJ, Liu, X, Lutschg, A, Zou, H

Cell 1997
28192157 Apaf-1: Regulation and function in cell death

Kheirollahi, A, Shakeri, R, Davoodi, J

Biochimie 2017
23521171 Changes in Apaf-1 conformation that drive apoptosome assembly

Eschenburg, S, Akey, CW, Reubold, TF, Topf, M, Yuan, S

Biochemistry 2013
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