APAF1

APAF1 Background

Apoptotic protease-activating factor 1 (APAF1) is a cytoplasmic protein in humans that is encoded by the APAF1 gene. APAF1 is a multi-domain adapter protein containing a caspase recruitment domain (CARD), followed by a nucleotide-binding ＆ oligomerization domain, a short helical motif, and several copies of the WD40 repeat domain ^[1][2][3]. ATPase domain of APAF1 is homologous to CED-4 in Caenorhabditis elegans. APAF1 normally presents an inactive monomer with locked conformation bound to dATP or ATPT ^[4]. During the intrinsic or mitochondrial pathway of apoptosis, APAF1 oligomerizes in the presence of dATP in response to cytochrome c release and recruits procaspase-9 ＆ caspase-3 to form apoptosome, eventually leading to apoptosis. APAF1 is, therefore, a crucial player in development due to its mediation of the mitochondria-dependent apoptosis. Although no alterations were observed in heterozygous mice, APAF1 deficient embryos died between embryonic day 16 and postnatal day 0 ^[5]. Abnormal Apaf-/- embryos were found at embryonic day 11.5, and later they showed alterations of the development of many organs ^[5]. The hypomorphic allele of APAF1 has reported causing reduced levels of the normal APAF1 transcript, thus affecting the neural tube development and fog (forebrain overgrowth) ^[6][7]. Results showed that either the absence of APAF1 or downregulation of APAF1 (below 50%) is deleterious for the development causing milder effects compatible with life and with possible links to human diseases ^[8]. Moreover, Soengas and his coworkers found that APAF1 or caspase-9 inactivation substitutes p53 loss in promoting the oncogenic transformation of myc-expressing cells by analyzed p53-null, Apaf1-null, and caspase-9-null MEFs ^[9]. Frame-shift mutations in the APAF1 gene were detected at low frequencies (13-15%) in gastrointestinal cancer (microsatellite mutator phenotype) ^[10].

[1] Zou H, Henzel WJ, et al. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3 [J]. Cell. Aug 1997, 90 (3): 405–13.
[2] Riedl SJ, Li W, et al. Structure of the apoptotic protease-activating factor 1 bound to ADP [J]. Nature. 2005 Apr 14; 434(7035):926-33.
[3] Yu X, Acehan D, et al. A structure of the human apoptosome at 12.8 A resolution provides insights into this cell death platform [J]. Structure. 2005 Nov; 13(11):1725-35.
[4] Kim HE, Du F, et al. Formation of apoptosome is initiated by cytochrome c-induced dATP hydrolysis and subsequent nucleotide exchange on Apaf-1 [J]. Proc Natl Acad Sci U S A. 2005 Dec 6; 102 (49):17545-50.
[5] Cecconi F., Alvarez-Bolado G., et al. Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development [J]. Cell., 1998, 94(6): 727-37.
[6] Honarpour N., Gilbert S.L., et al. Apaf-1 deficiency and neural tube closure defects are found in fog mice [J]. Proc. Natl. Acad. Sci. USA, 2001, 98: 9683-9687.
[7] Spellicy CJ, Norris J, et al. Key apoptotic genes APAF1 and CASP9 implicated in recurrent folate-resistant neural tube defects [J]. Eur J Hum Genet. 2018 Mar;26(3):420-427.
[8] Moreno S., Ferraro E., et al. Apaf1 reduced expression levels generate a mutant phenotype in adult brain and skeleton [J]. Cell Death Differ., 2002, 9: 340-342.
[9] Soengas M.S., Alarcon R.M., et al. Apaf-1 and Caspase-9 in p53-dependent apoptosis and tumor inhibition [J]. Science, 1999, 284:156-159.
[10] Yamamoto H., Gil J., et al. Frameshift mutations in Fas, Apaf-1, and Bcl-10 in gastrointestinal cancer of the microsatellite mutator phenotype [J]. Cell Death Differ., 2000, 7: 238-239.