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]
Identifiers
Symbols APAF1; CED4
External IDs OMIM: 602233 MGI: 1306796 HomoloGene: 7626 GeneCards: APAF1 Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 317 11783
Ensembl ENSG00000120868 ENSMUSG00000019979
UniProt O14727 Q4VZG8
RefSeq (mRNA) NM_001160 NM_001042558
RefSeq (protein) NP_001151 NP_001036023
Location (UCSC) Chr 12:
97.56 – 97.65 Mb		 Chr 10:
90.42 – 90.51 Mb
PubMed search [1] [2]

Apoptotic protease activating factor 1, also known as APAF1, is a human homolog of C. elegans CED-4 gene.[2][3][4] APAF-1 and CED-4 homologs have been found in all currently sequenced animal genomes.

Contents

Function

This gene encodes a cytoplasmic protein that forms one 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 caspase 9 preproprotein, 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

The first crystal structure of the first two (CARD and NB-ARC) domains of the Apaf-1 protein PDB 1z6t was solved in the laboratory of Yigong Shi.[6] It 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.

Discovery

The Apaf-1 protein was identified by Xiaodong Wang.[3]

Interactions

APAF1 has been shown to interact with NLRP1,[7] Caspase-9,[7][8][9][10][11] APIP,[8] BCL2-like 1[10][11] and HSPA4.[12]

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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2020445. 
  2. ^ a b "Entrez Gene: APAF1 apoptotic peptidase activating factor 1". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=317. 
  3. ^ a b Zou H, Henzel WJ, Liu X, Lutschg A, Wang X (August 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". Cytogenet. Cell Genet. 87 (3-4): 252–3. doi:10.1159/000015436. PMID 10702682. 
  5. ^ Pop C, Timmer J, Sperandio S, Salvesen GS (April 2006). "The apoptosome activates caspase-9 by dimerization". Mol. 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 (April 2005). "Structure of the apoptotic protease-activating factor 1 bound to ADP". Nature 434 (7035): 926–33. doi:10.1038/nature03465. PMID 15829969. 
  7. ^ a b Chu, Z L; Pio F, Xie Z, Welsh K, Krajewska M, Krajewski S, Godzik A, Reed J C (Mar. 2001). "A novel enhancer of the Apaf1 apoptosome involved in cytochrome c-dependent caspase activation and apoptosis". J. Biol. Chem. (United States) 276 (12): 9239–45. doi:10.1074/jbc.M006309200. ISSN 0021-9258. PMID 11113115. 
  8. ^ a b Cho, Dong-Hyung; Hong Yeon-Mi, Lee Ho-June, Woo Ha-Na, Pyo Jong-Ok, Mak Tak W, Jung Yong-Keun (Sep. 2004). "Induced inhibition of ischemic/hypoxic injury by APIP, a novel Apaf-1-interacting protein". J. Biol. Chem. (United States) 279 (38): 39942–50. doi:10.1074/jbc.M405747200. ISSN 0021-9258. PMID 15262985. 
  9. ^ Li, P; Nijhawan D, Budihardjo I, Srinivasula S M, Ahmad M, Alnemri E S, Wang X (Nov. 1997). "Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade". Cell (UNITED STATES) 91 (4): 479–89. doi:10.1016/S0092-8674(00)80434-1. ISSN 0092-8674. PMID 9390557. 
  10. ^ a b Hu, Y; Benedict M A, Wu D, Inohara N, Núñez G (Apr. 1998). "Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 95 (8): 4386–91. doi:10.1073/pnas.95.8.4386. ISSN 0027-8424. PMC 22498. PMID 9539746. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=22498. 
  11. ^ a b Pan, G; O'Rourke K, Dixit V M (Mar. 1998). "Caspase-9, Bcl-XL, and Apaf-1 form a ternary complex". J. Biol. Chem. (UNITED STATES) 273 (10): 5841–5. doi:10.1074/jbc.273.10.5841. ISSN 0021-9258. PMID 9488720. 
  12. ^ Saleh, A; Srinivasula S M, Balkir L, Robbins P D, Alnemri E S (Aug. 2000). "Negative regulation of the Apaf-1 apoptosome by Hsp70". Nat. Cell Biol. (ENGLAND) 2 (8): 476–83. doi:10.1038/35019510. ISSN 1465-7392. PMID 10934467. 

Further reading