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FLASH GENE
Symbol APAF1 contributors: mct/npt/pgu - updated : 05-06-2013
HGNC name apoptotic peptidase activating factor 1
HGNC id 576
Location 12q23      Physical location : 99.039.077 - 99.129.204
Synonym name
  • apoptotic protease activating factor
  • C.elegans cell death 4 homolog
  • cytoplasmic scaffolding apoptotic protease activating factor
  • Synonym symbol(s) KIAA0413, CED4, APAF, APAF-1, DKFZp781B1145
    DNA
    TYPE functioning gene
    STRUCTURE 90.13 kb     27 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    Map cen - D12S327 - D12S1657 - APAF1 - D12S393 - D12S1706 - D12S346 - qter
    Physical map
    FLJ44112 12q23.1 FLJ44112 protein LOC387876 12 LOC387876 LOC390352 12 similar to eukaryotic translation elongation factor 1 alpha 1; CTCL tumor antigen; translation elongation factor 1 alpha 1-like 14; prostate tumor-inducing protein 1; EF1a-like protein; glucocorticoid receptor AF-1 specific elongati NEDD1 12q22 neural precursor cell expressed, developmentally down-regulated 1 LOC121456 12q23.1 similar to solute carrier family 9, member 7; nonselective sodium potassium/proton exchanger; sodium/hydrogen exchanger 7 TMPO 12q22-q23.1 thymopoietin LOC341457 12q23.1 similar to peptidyl-Pro cis trans isomerase SLC25A3 12q22-q23.1 solute carrier family 25 (mitochondrial carrier; phosphate carrier), member 3 LOC387877 FLJ31051 APAF1 12q23 apoptotic protease activating factor EB-1 12q23.1-q23.2 E2a-Pbx1-associated protein MGC39520 12q23.2 hypothetical protein MGC39520 LOC387878 12 similar to ribosomal protein S4, X-linked KIAA0701 12q23.1-q23.3 similar to ribosomal protein S4, X-linked DKFZp434M0331 12q23.3 hypothetical protein DKFZp434M0331 ACTR6 12q23.3 actin-related protein 6 FLJ33505 12q23.3 hypothetical protein FLJ33505 FLJ10074 12q23.3 hypothetical protein FLJ10074 SLC17A8 12q23.3 solute carrier family 17 (sodium-dependent inorganic phosphate cotransporter), member 8 NR1H4 12q21.3 nuclear receptor subfamily 1, group H, member 4 LOC283431 12q23.3 hypothetical protein LOC283431 PIGAP1 12q21 phosphatidylinositol glycan, class A, pseudogene 1
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    26 - 7042 135 1194 - 2007 17348858
    27 - 7171 140 1237 - 2007 17348858
    27 - 7204 141 1248 - 2007 17348858
    26 - 7075 137 1205 - 2007 17348858
    8 - 4559 37 338 - 2007 17348858
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    blood / hematopoieticspleen   highly
    Endocrineparathyroid   highly
    Hearing/Equilibriumear   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / Hematopoietic    
    Lymphoid    
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticleukocyte
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N terminal CARD (caspase recruitment domain), CARD-NOD domain, directly interacting with the NOD domains of NAIP
  • twelve WD repeats (an insertion of 11 repeats between the CARD
  • ATPase domains and another 43AA insertion creating an additional WD-40 repeat)
  • a poly Ser domain (95-98 AA) and a NB-ARC domain (AA 93 to 403)
  • a CED4 domain involved in interaction with UTP6 , and that directly binds to the central domain of NUP107 in an ATR-regulated, phosphorylation-dependent manner
  • a central nucleotide-binding oligomerization domain
  • multiple WD40 domain repeats at the C-terminus that bind to Cytochrome C
  • mono polymer heteromer
    HOMOLOGY
    interspecies ortholog to C.elegans CED3 (NH2 terminal) and CED4
    Homologene
    FAMILY
  • WD (TRP-ASP) repeats (mediating protein protein interactions) family
  • CATEGORY adaptor , enzyme
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus
    basic FUNCTION
  • functions as an adaptor in an 700-kDa multiprotein complex (named the apoptosome) to mediate the activation of caspase-9
  • activating apoptosis caspase 9 and APF1 complex apoptosome in presence of cytopchrome C and ATP-leading to activation of caspase 3 and so to apoptosis
  • induced NF kappaB and NICK signaling molecules
  • hemoglobin scavenger receptor
  • might have a hitherto unsuspected role in the maintenance of genomic stability and cell cycle arrest, independent from its function in the apoptosis machinery
  • caspase-activating complex, APAF1 plays a central role in the mitochondrial caspase activation pathway of apoptosis
  • essential factor for cytochrome c-driven caspase activation during mitochondrial apoptosis but has also an apoptosis-unrelated function
  • implication in DNA damage-induced cell-cycle arrest (exerts two distinct, phylogenetically conserved roles in response to mitochondrial membrane permeabilization and DNA damage)
  • involvement in melanoma progression and chemoresistance
  • playing a necessary role for the cleavage or activation of all procaspases and the promotion of mitochondrial apoptotic events induced by genotoxic drugs
  • essential component of the apoptosome, the molecular complex assembled in response to mitochondrial cytochrome c release that promotes caspase activation
  • role in the maintenance of genomic stability, independently from its function in the cell death machinery
  • does not require energy from nucleotide hydrolysis to eventually form the apoptosome
  • key regulator gene of apoptosis, located downstream from TP53
  • having a non-apoptosis-related role in the pathology of protein-aggregation-dependent neurodegenerative diseases such as Huntington disease
  • required for minocycline-dependent inhibition of cell death
  • might potentially serve as a direct or indirect sensor or modulator of ER/mitochondria metabolic condition
  • relays the death signal in the mitochondrial pathway of apoptosis
  • main component of the apoptosome, and a crucial factor in the mitochondria-dependent death pathway
  • acts by regulating the recruitment of UTP6, with which it interacts, to the centrosome
  • might also be considered a pro-survival molecule, whose absence impairs cell performance and causes a higher responsiveness to stressful conditions
  • involved in the DNA damage response through cell-cycle arrest induced by genotoxic stress
  • crucial role of APAF1 nuclear relocalization in mediating cell-cycle arrest induced by genotoxic stress
  • CELLULAR PROCESS cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS development , immunity/defense
    text neurogenesis
    PATHWAY
    metabolism
    signaling
    a component
  • forming a large multimeric complex the apoptosome, dATP dependent with cytochrome C1 (CYC1) and the initiator of apoptosis caspase 9, that activates caspase 3
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • caspase 9 (by their NH2 terminal CED3 homologous domain) in the presence of cytochrome C1 and ATP
  • mediating the endocytosis of the hemoglobin-haptoglobin complex
  • interacting with RIPK2 and potentially inducing NF-Kappa B activity through TRAF6 and NIKs (NF-Kappa B inducing kinase)
  • target of TP53 in DNA damage-induced apoptosis
  • during apoptosis, binds cytochrome c released from mitochondria to the cytosol
  • UACA is a APAF1-binding proapoptotic protein involved in apoptosome-mediated apoptosis
  • oxidative modification of CASP9 facilitates its activation via disulfide-mediated interaction with APAF1
  • NAIP interacts with the NOD domain of APAF1, through its NOD domain
  • in addition to APAF1 or apoptosome formation, DIABLO is also essential for MTCH1-induced apoptosis
  • APAF1 associates with the nucleoporin NUP107 and this association is necessary for APAF1 nuclear import
  • cell & other
  • cytochrome C
  • REGULATION
    inhibited by not inhibited by binding to BCL2
    repressed by minocycline, which inhibits intrinsic (mitochondrial-mediated) but not extrinsic-mediated apoptosis activation through an inhibitory effect on APAF1 activity
    Other acute phase regulated
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --low  
    associated with tumour progression and adverse prognosis in colorectal cancer
    tumoral     --over  
    is related to an undifferentiated state in the testicular germ cell tumor pathway
    constitutional       loss of function
    results in an accumulation of neural progenitor cells (NPCs) in the developing central nervous system and thus, in perinatal lethality
    constitutional     --low  
    APAF1-deficient cells are less prone to developing aggregates than are wild-type cells, thereby supporting the involvement of APAF1 in a mammalian model of polyQ-related diseases
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurologyneurodegenerativehuntington chorea
    minocycline inhibits cell death and decreases mutant Huntingtin aggregation by targeting APAF1
    ANIMAL & CELL MODELS
  • murine Apaf1 null die at E16.5 day with craniofacial malformation, brain overgrowth, lens and retina alteration but persistence of interdigital webs and reduced apoptosis in fibroblasts
  • a Drosophila model of Huntington disease shows that inactivation of the dark gene (Drosophila Apaf-1 related killer) suppresses the formation of polyQ aggregates and diminishes the associated pathogenesis