APAF1

Apoptotic peptidase activating factor 1
Rainbow colored cartoon diagram (N-terminus = blue, C-terminus = red) of the crystallographic structure of the CARD domain of human APAF1.[1]
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1C15​, 1CWW​, 1CY5​, 1Z6T​, 2P1H​, 2YGS​, 3J2T​, 3YGS​, 4RHW​
Identifiers
Symbols	APAF1 ; APAF-1; CED4
External IDs	OMIM: 602233 MGI: 1306796 HomoloGene: 7626 ChEMBL: 1795093 GeneCards: APAF1 Gene
Gene ontology Molecular function • nucleotide binding • protein binding • ATP binding • cysteine-type endopeptidase activator activity involved in apoptotic process • heat shock protein binding • identical protein binding • ADP binding Cellular component • nucleus • cytosol • apoptosome • extracellular exosome Biological process • response to hypoxia • neural tube closure • apoptotic process • activation of cysteine-type endopeptidase activity involved in apoptotic process • nervous system development • aging • response to nutrient • activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c • cardiac muscle cell apoptotic process • programmed cell death • cell differentiation • forebrain development • glial cell apoptotic process • regulation of apoptotic process • positive regulation of apoptotic process • protein homooligomerization • neuron apoptotic process • intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress • cellular response to transforming growth factor beta stimulus • response to G1 DNA damage checkpoint signaling • intrinsic apoptotic signaling pathway • regulation of apoptotic DNA fragmentation • positive regulation of apoptotic signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	317	11783
Ensembl	ENSG00000120868	ENSMUSG00000019979
UniProt	O14727	O88879
RefSeq (mRNA)	NM_001160	NM_001042558
RefSeq (protein)	NP_001151	NP_001036023
Location (UCSC)	Chr 12: 98.65 – 98.74 Mb	Chr 10: 90.99 – 91.08 Mb
PubMed search

Apoptotic protease activating factor 1, also known as APAF1, is a human homolog of C. elegans CED-4 gene.^[2][3][4]

Function

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.^[5] Activated caspase 9 stimulates the subsequent caspase cascade that commits the cell to apoptosis.

Alternative splicing results in several transcript variants encoding different isoforms.^[2]

Structure

APAF1 contains a Greek key motif composed of six helices, a Rossman fold nucleotide binding domains, a short helical motif and a winged-helix domain.^[6] It contains a CARD domain with a

Interactions

APAF1 has been shown to interact with:

• APIP,^[7]
• BCL2-like 1^[8][9]
• Caspase-9,^{[10][7][11][8][9]}
• HSPA4,^[12] and
• NLRP1.^[10]

References

1. PDB: 2p1h​; Milam SL, Nicely NI, Feeney B, Mattos C, Clark AC (May 2007). "Rapid folding and unfolding of Apaf-1 CARD". J. Mol. Biol. 369 (1): 290–304. doi:10.1016/j.jmb.2007.02.105. PMC 2020445. PMID 17408690.
2. "Entrez Gene: APAF1 apoptotic peptidase activating factor 1".
3. 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.
4. 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.
5. 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.
6. 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. doi:10.1038/nature03465. PMID 15829969.
7. 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.
8. 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. doi:10.1073/pnas.95.8.4386. PMC 22498. PMID 9539746.
9. 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.
10. 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.
11. 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.
12. 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.

Further reading

• 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. 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.
• 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.
• 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.
• 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. 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. doi:10.1038/21124. PMID 10376594.
• 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.