Biology:APAF1

Short description: Mammalian protein found in Homo sapiens

Generic protein structure example

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

Function

The protein was identified in the laboratory of Xiaodong Wang as an activator of caspase-3 in the presence of cytochromeC and dATP. 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. Activated caspase-9 stimulates the subsequent caspase cascade that commits the cell to apoptosis.

Alternative splicing results in several transcript variants encoding different isoforms.

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.

Interactions

APAF1 has been shown to interact with:

• APIP,
• BCL2-like 1
• Caspase-9,
• HSPA4, and
• NLRP1.

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.

Further reading

• "The WD repeat: a common architecture for diverse functions". Trends in Biochemical Sciences 24 (5): 181–5. May 1999. doi:10.1016/S0968-0004(99)01384-5. PMID 10322433. 
• "Diva vaccines that reduce virus transmission". Journal of Biotechnology 73 (2–3): 195–205. Aug 1999. doi:10.1016/S0168-1656(99)00121-2. PMID 10486928. 
• "Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones". DNA Research 9 (3): 99–106. Jun 2002. doi:10.1093/dnares/9.3.99. PMID 12168954. 
• "Role of Apaf-1, a key regulator of apoptosis, in melanoma progression and chemoresistance". Experimental Dermatology 14 (11): 811–8. Nov 2005. doi:10.1111/j.1600-0625.2005.00360.x. PMID 16232302. 
• "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. doi:10.1016/S0092-8674(00)80501-2. PMID 9267021. 
• "Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade". Cell 91 (4): 479–89. Nov 1997. doi:10.1016/S0092-8674(00)80434-1. PMID 9390557. 
• "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. doi:10.1093/dnares/4.5.307. PMID 9455477. 
• "Caspase-9, Bcl-XL, and Apaf-1 form a ternary complex". The Journal of Biological Chemistry 273 (10): 5841–5. Mar 1998. doi:10.1074/jbc.273.10.5841. PMID 9488720. 
• "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. doi:10.1073/pnas.95.8.4386. PMID 9539746. Bibcode: 1998PNAS...95.4386H. 
• "Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization". Molecular Cell 1 (7): 949–57. Jun 1998. doi:10.1016/S1097-2765(00)80095-7. PMID 9651578. 
• "Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development". Cell 94 (6): 727–37. Sep 1998. doi:10.1016/S0092-8674(00)81732-8. PMID 9753320. 
• "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. doi:10.1074/jbc.273.49.32479. PMID 9829980. 
• "WD-40 repeat region regulates Apaf-1 self-association and procaspase-9 activation". The Journal of Biological Chemistry 273 (50): 33489–94. Dec 1998. doi:10.1074/jbc.273.50.33489. PMID 9837928. 
• "Boo, a novel negative regulator of cell death, interacts with Apaf-1". The EMBO Journal 18 (1): 167–78. Jan 1999. doi:10.1093/emboj/18.1.167. PMID 9878060. 
• "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. doi:10.1083/jcb.144.2.281. PMID 9922454. 
• "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. doi:10.1074/jbc.274.17.11549. PMID 10206961. 
• "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. doi:10.1074/jbc.274.25.17941. PMID 10364241. 
• "Structural basis of procaspase-9 recruitment by the apoptotic protease-activating factor 1". Nature 399 (6736): 549–57. Jun 1999. doi:10.1038/21124. PMID 10376594. Bibcode: 1999Natur.399..549Q. 
• "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. doi:10.1006/mcne.1999.0758. PMID 10383829.