APAF1
Олигомерный Apaf-1 опосредует цитохром с-зависимую автокаталитическую активацию про-каспазы-9 (Apaf-3), что приводит к активации каспазы-3 и апоптозу. Для активации требуется ATP. Изоформа 6 менее эффективна в индуцировании апоптоза.
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. 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. 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. Abnormal Apaf-/- embryos were found at embryonic day 11.5, and later they showed alterations of the development of many organs. 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). 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. 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. Frame-shift mutations in the APAF1 gene were detected at low frequencies (13-15%) in gastrointestinal cancer (microsatellite mutator phenotype). |
