APAF1 explained

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

Function

The protein was identified in the laboratory of Xiaodong Wang as an activator of caspase-3 in the presence of cytochromeC and dATP.^[3] 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.^[4] 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.^[6]

Interactions

APAF1 has been shown to interact with:

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

Further reading

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

Notes and References

1. Zou H, Henzel WJ, Liu X, Lutschg A, Wang X . 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 . Aug 1997 . 9267021 . 10.1016/S0092-8674(00)80501-2 . 18105320 . free .
2. Kim H, Jung YK, Kwon YK, Park SH . 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 . 1999 . 10702682 . 10.1159/000015436 . 10377371 .
3. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X . Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade . Cell . 91 . 4 . 479–89 . Nov 1997 . 9390557 . 10.1016/s0092-8674(00)80434-1. 14321446 . free .
4. Pop C, Timmer J, Sperandio S, Salvesen GS . The apoptosome activates caspase-9 by dimerization . Molecular Cell . 22 . 2 . 269–75 . Apr 2006 . 16630894 . 10.1016/j.molcel.2006.03.009 . free .
5. Web site: Entrez Gene: APAF1 apoptotic peptidase activating factor 1.
6. Riedl SJ, Li W, Chao Y, Schwarzenbacher R, Shi Y . Structure of the apoptotic protease-activating factor 1 bound to ADP . Nature . 434 . 7035 . 926–33 . Apr 2005 . 15829969 . 10.1038/nature03465 . 2005Natur.434..926R . 4355459 .
7. Cho DH, Hong YM, Lee HJ, Woo HN, Pyo JO, Mak TW, Jung YK . Induced inhibition of ischemic/hypoxic injury by APIP, a novel Apaf-1-interacting protein . The Journal of Biological Chemistry . 279 . 38 . 39942–50 . Sep 2004 . 15262985 . 10.1074/jbc.M405747200 . free .
8. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X . Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade . Cell . 91 . 4 . 479–89 . Nov 1997 . 9390557 . 10.1016/s0092-8674(00)80434-1. 14321446 . free .
9. Hu Y, Benedict MA, Wu D, Inohara N, Núñez G . 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 . Apr 1998 . 9539746 . 22498 . 10.1073/pnas.95.8.4386. 1998PNAS...95.4386H . free .
10. Pan G, O'Rourke K, Dixit VM . Caspase-9, Bcl-XL, and Apaf-1 form a ternary complex . The Journal of Biological Chemistry . 273 . 10 . 5841–5 . Mar 1998 . 9488720 . 10.1074/jbc.273.10.5841. free .
11. Saleh A, Srinivasula SM, Balkir L, Robbins PD, Alnemri ES . Negative regulation of the Apaf-1 apoptosome by Hsp70 . Nature Cell Biology . 2 . 8 . 476–83 . Aug 2000 . 10934467 . 10.1038/35019510 . 20374981 .
12. Chu ZL, Pio F, Xie Z, Welsh K, Krajewska M, Krajewski S, Godzik A, Reed JC . 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 . Mar 2001 . 11113115 . 10.1074/jbc.M006309200 . free .