APAF1

APAF1
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	1C15, 1CWW, 1CY5, 1Z6T, 2P1H, 2YGS, 3J2T, 3YGS, 4RHW, 3JBT
Identifiers
Aliases	APAF1, APAF-1, CED4, apoptotic peptidase activating factor 1
External IDs	OMIM: 602233 MGI: 1306796 HomoloGene: 7626 GeneCards: APAF1
Gene location (Human)
Chr.	Chromosome 12 (human)
End	98,735,433 bp
Gene location (Mouse)
Chr.	Chromosome 10 (mouse)
End	91,082,770 bp
RNA expression pattern
	Top expressed in
	monocyte; ; blood; ; bone marrow cells; ; ganglionic eminence; ; Achilles tendon; ; trabecular bone; ; tibia; ; Brodmann area 9; ; germinal epithelium; ; amygdala;
	Top expressed in
	dermis; ; ureter; ; jejunum; ; vas deferens; ; ileum; ; cumulus cell; ; abdominal wall; ; saccule; ; duodenum; ; intestinal epithelium;
	More reference expression data
	; ; ; ;
	More reference expression data
Gene ontology
Molecular function	heat shock protein binding; ADP binding; protein binding; identical protein binding; ATP binding; nucleotide binding; cysteine-type endopeptidase activator activity involved in apoptotic process;
Cellular component	cytoplasm; cytosol; extracellular exosome; nucleus; apoptosome; extracellular region; secretory granule lumen; ficolin-1-rich granule lumen; protein-containing complex;
Biological process	cellular response to transforming growth factor beta stimulus; neuron apoptotic process; regulation of apoptotic process; cell differentiation; response to hypoxia; response to nutrient; response to G1 DNA damage checkpoint signaling; human ageing; positive regulation of apoptotic signaling pathway; glial cell apoptotic process; nervous system development; multicellular organism development; cardiac muscle cell apoptotic process; intrinsic apoptotic signaling pathway; intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; neural tube closure; brain development; positive regulation of apoptotic process; apoptotic signaling pathway; forebrain development; regulation of apoptotic DNA fragmentation; protein homooligomerization; activation of cysteine-type endopeptidase activity involved in apoptotic process; activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c; apoptotic process; neutrophil degranulation; negative regulation of G0 to G1 transition; kidney development;
	Sources:Amigo / QuickGO
Orthologs
	317
	11783
	ENSG00000120868
	ENSMUSG00000019979
	O14727
	O88879
	NM_001160; NM_013229; NM_181861; NM_181868; NM_181869
	NM_001042558; NM_001282947; NM_009684
	NP_001151; NP_037361; NP_863651; NP_863658; NP_863659
	NP_001036023; NP_001269876; NP_033814
	Wikidata
View/Edit Human	View/Edit Mouse

Apoptotic protease activating factor 1, also known as APAF1, is a human homolog of C. elegans CED-4 gene.^[5]^[6]^[7]

Function

The protein was identified in the laboratory of Xiaodong Wang as an activator of caspase-3 in the presence of cytochromeC and dATP.^[8] This gene encodes a cytoplasmic protein that forms one of the central hubs in the apoptosis regulatory network. This protein contains (from the N terminal) a caspase recruitment domain (CARD), an ATPase domain (NB-ARC), few short helical domains and then several copies of the WD40 repeat domain. Upon binding cytochrome c and dATP, this protein forms an oligomeric apoptosome. The apoptosome binds and cleaves Procaspase-9 protein, releasing its mature, activated form. The precise mechanism for this reaction is still debated though work published by Guy Salvesen suggests that the apoptosome may induce caspase-9 dimerization and subsequent autocatalysis.^[9] Activated caspase-9 stimulates the subsequent caspase cascade that commits the cell to apoptosis.

Alternative splicing results in several transcript variants encoding different isoforms.^[5]

Structure

APAF1 contains a CARD domain with a Greek key motif composed of six helices, a Rossman fold nucleotide binding domains, a short helical motif and a winged-helix domain.^[10]

Interactions

APAF1 has been shown to interact with:

APIP,^[11]
BCL2-like 1^[12]^[13]
Caspase-9,^[14]^[11]^[15]^[12]^[13]
HSPA4,^[16] and
NLRP1.^[14]

References

^ a b c GRCh38: Ensembl release 89: ENSG00000120868 – Ensembl, May 2017
^ a b c GRCm38: Ensembl release 89: ENSMUSG00000019979 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ a b "Entrez Gene: APAF1 apoptotic peptidase activating factor 1".
^ Zou H, Henzel WJ, Liu X, Lutschg A, Wang X (Aug 1997). "Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3". Cell. 90 (3): 405–13. doi:10.1016/S0092-8674(00)80501-2. PMID 9267021. S2CID 18105320.
^ Kim H, Jung YK, Kwon YK, Park SH (1999). "Assignment of apoptotic protease activating factor-1 gene (APAF1) to human chromosome band 12q23 by fluorescence in situ hybridization". Cytogenetics and Cell Genetics. 87 (3–4): 252–3. doi:10.1159/000015436. PMID 10702682. S2CID 10377371.
^ Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (Nov 1997). "Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade". Cell. 91 (4): 479–89. doi:10.1016/s0092-8674(00)80434-1. PMID 9390557. S2CID 14321446.
^ Pop C, Timmer J, Sperandio S, Salvesen GS (Apr 2006). "The apoptosome activates caspase-9 by dimerization". Molecular Cell. 22 (2): 269–75. doi:10.1016/j.molcel.2006.03.009. PMID 16630894.
^ Riedl SJ, Li W, Chao Y, Schwarzenbacher R, Shi Y (Apr 2005). "Structure of the apoptotic protease-activating factor 1 bound to ADP". Nature. 434 (7035): 926–33. Bibcode:2005Natur.434..926R. doi:10.1038/nature03465. PMID 15829969. S2CID 4355459.
^ a b Cho DH, Hong YM, Lee HJ, Woo HN, Pyo JO, Mak TW, Jung YK (Sep 2004). "Induced inhibition of ischemic/hypoxic injury by APIP, a novel Apaf-1-interacting protein". The Journal of Biological Chemistry. 279 (38): 39942–50. doi:10.1074/jbc.M405747200. PMID 15262985.
^ a b Hu Y, Benedict MA, Wu D, Inohara N, Núñez G (Apr 1998). "Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation". Proceedings of the National Academy of Sciences of the United States of America. 95 (8): 4386–91. Bibcode:1998PNAS...95.4386H. doi:10.1073/pnas.95.8.4386. PMC 22498. PMID 9539746.
^ a b Pan G, O'Rourke K, Dixit VM (Mar 1998). "Caspase-9, Bcl-XL, and Apaf-1 form a ternary complex". The Journal of Biological Chemistry. 273 (10): 5841–5. doi:10.1074/jbc.273.10.5841. PMID 9488720.
^ a b Chu ZL, Pio F, Xie Z, Welsh K, Krajewska M, Krajewski S, Godzik A, Reed JC (Mar 2001). "A novel enhancer of the Apaf1 apoptosome involved in cytochrome c-dependent caspase activation and apoptosis". The Journal of Biological Chemistry. 276 (12): 9239–45. doi:10.1074/jbc.M006309200. PMID 11113115.
^ Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (Nov 1997). "Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade". Cell. 91 (4): 479–89. doi:10.1016/s0092-8674(00)80434-1. PMID 9390557. S2CID 14321446.
^ Saleh A, Srinivasula SM, Balkir L, Robbins PD, Alnemri ES (Aug 2000). "Negative regulation of the Apaf-1 apoptosome by Hsp70". Nature Cell Biology. 2 (8): 476–83. doi:10.1038/35019510. PMID 10934467. S2CID 20374981.

External links

Human APAF1 genome location and APAF1 gene details page in the UCSC Genome Browser.
Overview of all the structural information available in the PDB for UniProt: O14727 (Apoptotic protease-activating factor 1) at the PDBe-KB.

Smith TF, Gaitatzes C, Saxena K, Neer EJ (May 1999). "The WD repeat: a common architecture for diverse functions". Trends in Biochemical Sciences. 24 (5): 181–5. doi:10.1016/S0968-0004(99)01384-5. PMID 10322433.
van Oirschot JT (Aug 1999). "Diva vaccines that reduce virus transmission". Journal of Biotechnology. 73 (2–3): 195–205. doi:10.1016/S0168-1656(99)00121-2. PMID 10486928.
Nakajima D, Okazaki N, Yamakawa H, Kikuno R, Ohara O, Nagase T (Jun 2002). "Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones". DNA Research. 9 (3): 99–106. CiteSeerX 10.1.1.500.923. doi:10.1093/dnares/9.3.99. PMID 12168954.
Campioni M, Santini D, Tonini G, Murace R, Dragonetti E, Spugnini EP, Baldi A (Nov 2005). "Role of Apaf-1, a key regulator of apoptosis, in melanoma progression and chemoresistance". Experimental Dermatology. 14 (11): 811–8. doi:10.1111/j.1600-0625.2005.00360.x. PMID 16232302. S2CID 45588573.
Zou H, Henzel WJ, Liu X, Lutschg A, Wang X (Aug 1997). "Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3". Cell. 90 (3): 405–13. doi:10.1016/S0092-8674(00)80501-2. PMID 9267021. S2CID 18105320.
Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (Nov 1997). "Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade". Cell. 91 (4): 479–89. doi:10.1016/S0092-8674(00)80434-1. PMID 9390557. S2CID 14321446.
Ishikawa K, Nagase T, Nakajima D, Seki N, Ohira M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (Oct 1997). "Prediction of the coding sequences of unidentified human genes. VIII. 78 new cDNA clones from brain which code for large proteins in vitro". DNA Research. 4 (5): 307–13. doi:10.1093/dnares/4.5.307. PMID 9455477.
Pan G, O'Rourke K, Dixit VM (Mar 1998). "Caspase-9, Bcl-XL, and Apaf-1 form a ternary complex". The Journal of Biological Chemistry. 273 (10): 5841–5. doi:10.1074/jbc.273.10.5841. PMID 9488720.
Hu Y, Benedict MA, Wu D, Inohara N, Núñez G (Apr 1998). "Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation". Proceedings of the National Academy of Sciences of the United States of America. 95 (8): 4386–91. Bibcode:1998PNAS...95.4386H. doi:10.1073/pnas.95.8.4386. PMC 22498. PMID 9539746.
Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Alnemri ES (Jun 1998). "Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization". Molecular Cell. 1 (7): 949–57. doi:10.1016/S1097-2765(00)80095-7. PMID 9651578.
Cecconi F, Alvarez-Bolado G, Meyer BI, Roth KA, Gruss P (Sep 1998). "Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development". Cell. 94 (6): 727–37. doi:10.1016/S0092-8674(00)81732-8. PMID 9753320.
Inohara N, Gourley TS, Carrio R, Muñiz M, Merino J, Garcia I, Koseki T, Hu Y, Chen S, Núñez G (Dec 1998). "Diva, a Bcl-2 homologue that binds directly to Apaf-1 and induces BH3-independent cell death". The Journal of Biological Chemistry. 273 (49): 32479–86. doi:10.1074/jbc.273.49.32479. PMID 9829980.
Hu Y, Ding L, Spencer DM, Núñez G (Dec 1998). "WD-40 repeat region regulates Apaf-1 self-association and procaspase-9 activation". The Journal of Biological Chemistry. 273 (50): 33489–94. doi:10.1074/jbc.273.50.33489. PMID 9837928.
Song Q, Kuang Y, Dixit VM, Vincenz C (Jan 1999). "Boo, a novel negative regulator of cell death, interacts with Apaf-1". The EMBO Journal. 18 (1): 167–78. doi:10.1093/emboj/18.1.167. PMC 1171112. PMID 9878060.
Slee EA, Harte MT, Kluck RM, Wolf BB, Casiano CA, Newmeyer DD, Wang HG, Reed JC, Nicholson DW, Alnemri ES, Green DR, Martin SJ (Jan 1999). "Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner". The Journal of Cell Biology. 144 (2): 281–92. doi:10.1083/jcb.144.2.281. PMC 2132895. PMID 9922454.
Zou H, Li Y, Liu X, Wang X (Apr 1999). "An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9". The Journal of Biological Chemistry. 274 (17): 11549–56. doi:10.1074/jbc.274.17.11549. PMID 10206961.
Saleh A, Srinivasula SM, Acharya S, Fishel R, Alnemri ES (Jun 1999). "Cytochrome c and dATP-mediated oligomerization of Apaf-1 is a prerequisite for procaspase-9 activation". The Journal of Biological Chemistry. 274 (25): 17941–5. doi:10.1074/jbc.274.25.17941. PMID 10364241.
Qin H, Srinivasula SM, Wu G, Fernandes-Alnemri T, Alnemri ES, Shi Y (Jun 1999). "Structural basis of procaspase-9 recruitment by the apoptotic protease-activating factor 1". Nature. 399 (6736): 549–57. Bibcode:1999Natur.399..549Q. doi:10.1038/21124. PMID 10376594. S2CID 4403525.
Drosopoulos NE, Walsh FS, Doherty P (Jun 1999). "A soluble version of the receptor-like protein tyrosine phosphatase kappa stimulates neurite outgrowth via a Grb2/MEK1-dependent signaling cascade". Molecular and Cellular Neurosciences. 13 (6): 441–9. doi:10.1006/mcne.1999.0758. PMID 10383829. S2CID 35458154.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000120868 – Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000019979 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[entrez-5] "Entrez Gene: APAF1 apoptotic peptidase activating factor 1".

[pmid9267021-6] Zou H, Henzel WJ, Liu X, Lutschg A, Wang X (Aug 1997). "Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3". Cell. 90 (3): 405–13. doi:10.1016/S0092-8674(00)80501-2. PMID 9267021. S2CID 18105320.

[pmid10702682-7] Kim H, Jung YK, Kwon YK, Park SH (1999). "Assignment of apoptotic protease activating factor-1 gene (APAF1) to human chromosome band 12q23 by fluorescence in situ hybridization". Cytogenetics and Cell Genetics. 87 (3–4): 252–3. doi:10.1159/000015436. PMID 10702682. S2CID 10377371.

[8] Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (Nov 1997). "Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade". Cell. 91 (4): 479–89. doi:10.1016/s0092-8674(00)80434-1. PMID 9390557. S2CID 14321446.

[pmid16630894-9] Pop C, Timmer J, Sperandio S, Salvesen GS (Apr 2006). "The apoptosome activates caspase-9 by dimerization". Molecular Cell. 22 (2): 269–75. doi:10.1016/j.molcel.2006.03.009. PMID 16630894.

[pmid15829969-10] Riedl SJ, Li W, Chao Y, Schwarzenbacher R, Shi Y (Apr 2005). "Structure of the apoptotic protease-activating factor 1 bound to ADP". Nature. 434 (7035): 926–33. Bibcode:2005Natur.434..926R. doi:10.1038/nature03465. PMID 15829969. S2CID 4355459.

[pmid15262985-11] Cho DH, Hong YM, Lee HJ, Woo HN, Pyo JO, Mak TW, Jung YK (Sep 2004). "Induced inhibition of ischemic/hypoxic injury by APIP, a novel Apaf-1-interacting protein". The Journal of Biological Chemistry. 279 (38): 39942–50. doi:10.1074/jbc.M405747200. PMID 15262985.

[pmid9539746-12] Hu Y, Benedict MA, Wu D, Inohara N, Núñez G (Apr 1998). "Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation". Proceedings of the National Academy of Sciences of the United States of America. 95 (8): 4386–91. Bibcode:1998PNAS...95.4386H. doi:10.1073/pnas.95.8.4386. PMC 22498. PMID 9539746.

[pmid9488720-13] Pan G, O'Rourke K, Dixit VM (Mar 1998). "Caspase-9, Bcl-XL, and Apaf-1 form a ternary complex". The Journal of Biological Chemistry. 273 (10): 5841–5. doi:10.1074/jbc.273.10.5841. PMID 9488720.

[pmid11113115-14] Chu ZL, Pio F, Xie Z, Welsh K, Krajewska M, Krajewski S, Godzik A, Reed JC (Mar 2001). "A novel enhancer of the Apaf1 apoptosome involved in cytochrome c-dependent caspase activation and apoptosis". The Journal of Biological Chemistry. 276 (12): 9239–45. doi:10.1074/jbc.M006309200. PMID 11113115.

[pmid9390557-15] Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (Nov 1997). "Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade". Cell. 91 (4): 479–89. doi:10.1016/s0092-8674(00)80434-1. PMID 9390557. S2CID 14321446.

[pmid10934467-16] Saleh A, Srinivasula SM, Balkir L, Robbins PD, Alnemri ES (Aug 2000). "Negative regulation of the Apaf-1 apoptosome by Hsp70". Nature Cell Biology. 2 (8): 476–83. doi:10.1038/35019510. PMID 10934467. S2CID 20374981.