APAF1 (Homo sapiens)

Description [+]

Synonyms: APAF1, CED4
Species: Metazoa;Bilateria;Deuterostoma;Chordata;Vertebrata;Mammalia;Primates;Hominidae; Homo sapiens
Short gene description: Apoptotic protease-activating factor 1 (Apaf-1) [Source:UniProtKB/Swiss-Prot;Acc:O14727]
Family: CARD-containing protein : CARD adapter protein
Process: apoptosis,
Pathways: intrinsic pathway, post-mitochondrial caspase activation,
Criteria: manually curated
Curator comment:
Mouse ortholog(s): Apaf1
WIKI: APAF1-H_sapiens

References [+]

Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3.
Zou H, Henzel WJ, Liu X, Lutschg A, Wang X
We report here the purification and cDNA cloning of Apaf-1, a novel 130 kd protein from HeLa cell cytosol that participates in the cytochrome c-dependent activation of caspase-3. The NH2-terminal 85 amino acids of Apaf-1 show 21% identity and 53% similarity to the NH2-terminal prodomain of the Caenorhabditis elegans caspase, CED-3. This is followed by 320 amino acids that show 22% identity and 48% similarity to CED-4, a protein that is believed to initiate apoptosis in C. elegans. The COOH-terminal region of Apaf-1 comprises multiple WD repeats, which are proposed to mediate protein-protein interactions. Cytochrome c binds to Apaf-1, an event that may trigger the activation of caspase-3, leading to apoptosis. Cell. 1997 Aug 8;90(3):405-13.

Analysis of the composition, assembly kinetics and activity of native Apaf-1 apoptosomes.
Hill MM, Adrain C, Duriez PJ, Creagh EM, Martin SJ
The Apaf-1 apoptosome is a multi-subunit caspase-activating scaffold that is assembled in response to diverse forms of cellular stress that culminate in apoptosis. To date, most studies on apoptosome composition and function have used apoptosomes reassembled from recombinant or purified proteins. Thus, the precise composition of native apoptosomes remains unresolved. Here, we have used a one-step immunopurification approach to isolate catalytically active Apaf-1/caspase-9 apoptosomes, and have identified the major constituents of these complexes using mass spectrometry methods. Using this approach, we have also assessed the ability of putative apoptosome regulatory proteins, such as Smac/DIABLO and PHAPI, to regulate the activity of native apoptosomes. We show that Apaf-1, caspase-9, caspase-3 and XIAP are the major constituents of native apoptosomes and that cytochrome c is not stably associated with the active complex. We also demonstrate that the IAP-neutralizing protein Smac/DIABLO and the tumor-suppressor protein PHAPI can enhance the catalytic activity of apoptosome complexes in distinct ways. Surprisingly, PHAPI also enhanced the activity of purified caspase-3, suggesting that it may act as a co-factor for this protease. EMBO J. 2004 May 19;23(10):2134-45. Epub 2004 Apr 22.

References from Mouse ortholog(s):

Apaf1 is required for mitochondrial pathways of apoptosis and brain development.
Yoshida H, Kong YY, Yoshida R, Elia AJ, Hakem A, Hakem R, Penninger JM, Mak TW
Apoptosis is essential for the precise regulation of cellular homeostasis and development. The role in vivo of Apaf1, a mammalian homolog of C. elegans CED-4, was investigated in gene-targeted Apaf1-/- mice. Apaf1-deficient mice exhibited reduced apoptosis in the brain and striking craniofacial abnormalities with hyperproliferation of neuronal cells. Apaf1-deficient cells were resistant to a variety of apoptotic stimuli, and the processing of Caspases 2, 3, and 8 was impaired. However, both Apaf1-/- thymocytes and activated T lymphocytes were sensitive to Fas-induced killing, showing that Fas-mediated apoptosis in these cells is independent of Apaf1. These data indicate that Apaf1 plays a central role in the common events of mitochondria-dependent apoptosis in most death pathways and that this role is critical for normal development. Cell. 1998 Sep 18;94(6):739-50.

Structure & Sequence [+]

Pfam domains: (Pfam is a large collection of protein families.)

Source	Domain Name	Start	End
PFAM A	CARD	6	90
PFAM A	NB-ARC	129	414
PFAM A	WD40	605	643
PFAM A	WD40	647	685
PFAM A	WD40	689	729
PFAM A	WD40	733	771
PFAM A	WD40	872	910
PFAM A	WD40	1075	1113
PFAM A	WD40	1117	1155

Protein sequence [+]

Structure links:

Smartdomain prediction information: SM00320
Prosite motif and domain information: PS00678
Profile motif and domain profile information: PS50209
Profile motif and domain profile information: PS50082
Profile motif and domain profile information: PS50294
Interpro domain information: O14727
PFAM domain and domain family information: O14727
Protein 3D structures from PDB: 1C15 3YGS

Evolution [+]

View protein alignment and tree with Jalview:

Explore tree at phylomeDB: Click here.

Homologs list [+]

Name	Relationship	Species
APAF1	orthology	Chicken
APAF1	orthology	Chimpanzee
XR_027402.2	orthology	Cow
APAF_CANFA	orthology	Dog
APAF1	orthology	Fugu
APAF1	orthology	Gasterosteus
APAF1	orthology	Gorilla
Q8HXQ7_HORSE	orthology	Horse
APAF1	orthology	Lyzard
APAF1	orthology	Macaca
APAF1	orthology	Medaka
APAF1	orthology	Monodelphis
Apaf1	orthology	Mouse
APAF1	orthology	Orangutan
APAF1	orthology	Ornithorhynchus
APAF1	orthology	Rabbit
Apaf1	orthology	Rat
APAF1	orthology	Tetraodon
APAF1	orthology	Xenopus
APAF1	orthology	Zebra finch
apaf1	orthology	Zebrafish
A_aegypti_AAEL004526-PA	paralogy	Aedes
A_aegypti_AAEL001276-PA	paralogy	Aedes
A_aegypti_AAEL004364-PA	paralogy	Aedes
A_gambiae_AGAP004827-PA	paralogy	Anopheles
A_gambiae_AGAP009615-PA	paralogy	Anopheles
NP_001006166.1	paralogy	Chicken
NP_001026656.1	paralogy	Chicken
WDR3	paralogy	Chimpanzee
TEP1	paralogy	Chimpanzee
C_intestinalis_ENSCINP00000010464	paralogy	Ciona
C_intestinalis_ENSCINP00000019387	paralogy	Ciona
IPI00694068.2	paralogy	Cow
NP_001040084.1	paralogy	Cow
TEP1	paralogy	Cow
CG30116	paralogy	Fly
WDR3	paralogy	Fugu
TBL3	paralogy	Fugu
TBL3	paralogy	Gasterosteus
WDR3	paralogy	Horse
TEP1	paralogy	Horse
WDR3	paralogy	Human
TEP1	paralogy	Human
TEP1	paralogy	Macaca
TBL3	paralogy	Macaca
WDR3	paralogy	Macaca
WDR3	paralogy	Medaka
TBL3	paralogy	Monodelphis
WDR3	paralogy	Monodelphis
TEP1	paralogy	Monodelphis
Wdr3	paralogy	Mouse
WDR3	paralogy	Orangutan
WDR3	paralogy	Ornithorhynchus
Tep1	paralogy	Rat
NP_001101175.1	paralogy	Rat
WDR3	paralogy	Tetraodon
TBL3	paralogy	Tetraodon
qui-1	paralogy	Worm
wdr3	paralogy	Xenopus
TBL3	paralogy	Xenopus
TEP1	paralogy	Xenopus
UTP13	paralogy	Yeast
T_guttata_ENSTGUP00000006840	paralogy	Zebra finch
WDR3	paralogy	Zebra finch
wdr3	paralogy	Zebrafish

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Gene Ontology [+]

GO id	Name	Ontology type	Evidence
GO:0006952	defense response	biological_proccess	IEA
GO:0042981	regulation of apoptosis	biological_proccess	IEA
GO:0006915	apoptosis	biological_proccess	IEA
GO:0007399	nervous system development	biological_proccess	TAS
GO:0008635	activation of caspase activity by cytochrome c	biological_proccess	IDA
GO:0042981	regulation of apoptosis	biological_proccess	TAS
GO:0007275	multicellular organismal development	biological_proccess	IEA
GO:0007420	brain development	biological_proccess	IEA
GO:0006309	DNA fragmentation during apoptosis	biological_proccess	IEA
GO:0006919	activation of caspase activity	biological_proccess	IEA
GO:0001843	neural tube closure	biological_proccess	IEA
GO:0030900	forebrain development	biological_proccess	IEA
GO:0051402	neuron apoptosis	biological_proccess	IEA
GO:0005515	protein binding	mollecular_function	IEA
GO:0005524	ATP binding	mollecular_function	IEA
GO:0005515	protein binding	mollecular_function	IPI
GO:0008656	caspase activator activity	mollecular_function	NAS
GO:0000166	nucleotide binding	mollecular_function	TAS
GO:0042802	identical protein binding	mollecular_function	IEA
GO:0016505	apoptotic protease activator activity	mollecular_function	IEA
GO:0005622	intracellular	cell_component	IEA
GO:0005829	cytosol	cell_component	TAS
GO:0005737	cytoplasm	cell_component	IEA
GO:0005634	nucleus	cell_component	IEA
GO:0005625	soluble fraction	cell_component	IEA

Check GO Evidence Codes here

KEGG Pathways [+]

miRNAs [+]

miRNA	Regulation	Description	Pubmed
hsa-miR-21	downregulation by LNA antisense miRNA oligonucleot	All 18 genes showed, to varying degrees, increased mRNA expression levels upon miR-21 inhibition (Fig. 2B).	Ref.
hsa-miR-21	downregulation by LNA antisense miRNA oligonucleot	Following normalization and statistical analysis we found 737 transcripts with significantly different expression between the LNA-miR-21-transfected cells and the controls, of which 402 (55%) were up-regulated and 335 (45%) down-regulated upon miR-21 inhibition (Fig. 2A and supplemental Table S1).	Ref.

Information from other databases [+]

Gene related links:

Gene info from HGNC [?] :576
Gene related info from GeneCards [?] : APAF1
Ensembl genome browser [?] : ENSG00000120868
Expression info from Arrayexpress [?] : ENSG00000120868
Protein expression from Protein Atlas: [?] ENSG00000120868
Community gene edition from Wikigenes: [?] 317

Protein related links:

Uniprot protein info: O14727
PIR protein info: O14727
Protein interactions from IntAct: O14727

Gene and disease information from OMIM: (For a full disease description table, click here.)

OMIM gene information: 602233
OMIM disease information:

Other links

entrezgene: 317
refseq_dna: NM_181868
refseq_dna: NM_001160
refseq_dna: NM_181861
refseq_dna: NM_013229
refseq_dna: NM_181869
refseq_peptide: NP_863658
refseq_peptide: NP_001151
refseq_peptide: NP_863651
refseq_peptide: NP_037361
refseq_peptide: NP_863659

Click on [?] for more information.