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; OMA:APAF1 - orthologs
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12q23.1 Start 98,645,290 bp[1] End 98,735,433 bp[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)[2] Band 10 C2|10 45.47 cM Start 90,989,311 bp[2] End 91,082,770 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte ventricular zone blood bone marrow cells ganglionic eminence epithelium of colon granulocyte Achilles tendon trabecular bone testicle Top expressed in granulocyte dermis migratory enteric neural crest cell ureter jejunum vas deferens otic vesicle stroma of bone marrow gastrula ileum More reference expression data BioGPS 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 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 Species Human Mouse Entrez 317 11783 Ensembl ENSG00000120868 ENSMUSG00000019979 UniProt O14727 O88879 RefSeq (mRNA) NM_001160 NM_013229 NM_181861 NM_181868 NM_181869 NM_001042558 NM_001282947 NM_009684 RefSeq (protein) NP_001151 NP_037361 NP_863651 NP_863658 NP_863659 NP_001036023 NP_001269876 NP_033814 Location (UCSC) Chr 12: 98.65 – 98.74 Mb Chr 10: 90.99 – 91.08 Mb PubMed search [3] [4]
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.^{[citation needed]}

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

1. GRCh38: Ensembl release 89: ENSG00000120868 – Ensembl, May 2017
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.
5. "Entrez Gene: APAF1 apoptotic peptidase activating factor 1".
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

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. 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.