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The apoptosome is a large quaternary protein structure formed in the process of apoptosis. Its formation is triggered by the release of cytochrome c from the mitochondria in response to an internal (intrinsic) or external (extrinsic) cell death stimulus. Stimuli can vary from DNA damage and viral infection to developmental cues such as those leading to the degradation of a tadpole's tail. In mammalian cells, once cytochrome c is released, it binds to the cytosolic protein Apaf-1 to facilitate the formation of apoptosome. An early biochemical study suggests a two-to-one ratio of cytochrome c to apaf-1 for apoptosome formation. However, recent structural studies suggest the cytochrome c to apaf-1 ratio is one-to-one. It has also been shown that the nucleotide dATP as third component binds to apaf-1, however its exact role is still debated. The mammalian apoptosome had never been crystallized, but a human APAF-1/cytochrome-c apoptosome has been imaged at lower (2 nm) resolution by cryogenic transmission electron microscopy 10 years ago,〔Acehan D, Jiang X, Morgan DG, Heuser JE, Wang X, Akey CW "Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation." Mol Cell. 2002 Feb;9(2):423-32.〕 revealing a wheel-like particle with 7-fold symmetry. Recently, a medium resolution (9.5 Ångström) structure of human apoptosome was also solved by cryo-electron microscopy, which allows unambiguous inference for positions of all the APAF-1 domains (CARD, NBARC and WD40) and cytochrome c. There is also now a crystal structure of the monomeric, inactive Apaf-1 subunit (PDB 3SFZ).〔 Once formed, the apoptosome can then recruit and activate the inactive pro-caspase-9. Once activated, this initiator caspase can then activate effector caspases and trigger a cascade of events leading to apoptosis. ==History== The term Apoptosome was first introduced in Yoshihide Tsujimoto's 1998 paper "Role of Bcl-2 family proteins in apoptosis: apoptosomes or mitochondria?".〔Tsujimoto, Yoshihide. Role of Bcl-2 Family Proteins in Apoptosis: Apoptosomes or Mitochondria?" Genes to Cells 3.11 (1998): 697-707.〕 However, the Apoptosome was known before this time as a ternary complex. This complex involved caspase-9 and Bcl-XL which each bound a specific Apaf-1 domain. The formation of this complex was then believed to play a regulatory role in mammalian cell death.〔Pan, G., K. O'Rourke, and V. M. Dixit. Caspase-9, Bcl-XL, and Apaf-1 Form a Ternary Complex. Journal of Biological Chemistry 273 (1998): 5841-845.〕 In December of the same year, a further article was released in The Journal of Biological Chemistry stating that Apaf-1 is the regulator of apoptosis, through activation of procaspase-9.〔Hu, Ding, Spencer, and Nunez. WD-40 Repeat Region Regulates Apaf-1 Self-association and Procaspase-9 Activation. Journal of Biological Chemistry 273 (1998): 33489-3494〕 The criteria for an apoptosome were laid out in 1999. Firstly, it must be a large complex (greater than 1.3 million Daltons). Secondly its formation requires the hydrolysis of a high energy bond of ATP or dATP. And lastly it must activate procaspase-9 in its functional form. The formation of this complex is the point of no return, and apoptosis will occur. The stable APAF-1 and cytochrome mutimeric complex fit this description, and is now called the apoptosome.〔Zou, Li, Liu and Wang. An APAF-1z Cytochrome c Multimeric Complex Is a Functional Apoptosome That Activates Procaspase-9. Journal Biological Cemistry, 274(17) (1999: 11549-11556.〕 The apoptosome was thought to be a mutimeric complex for two reasons. Firstly, to bring multiple procaspase-9 molecules close together for cleavage. And secondly, to raise the threshold for apoptosis, therefore nonspecific leakage of cytochrome c would not result in apoptosis.〔 Once the apoptosome was established as the procaspase-9 activator, mutations within this pathway became an important research area. Some examples include human leukemia cells, ovarian cancer and viral infections.〔Jia, L. et al. Apaf-1 Protein Deficiency Confers Resistance to Cytochrome c-dependent Apoptosis in Human Leukemic Cells. Journal of The American Society of Hematology 98.2 (2001): 414-21〕〔Bitzer, M. et al. Caspase-8 and Apaf-1-independent Caspase-9 Activation in Sendai Virus-infected Cells. The Journal of Biological Chemistry 277 (2002): 29817-9824〕〔Wolf, B. et al. Defective Cytochrome c-dependent Caspase Activation in Ovarian Cancer Cell Lines Due to Diminished or Absent Apoptotic Protease Activating Factor-1 Activity. The Journal of Biological Chemistry 276 (2001): 34244-4251〕 Current research areas for this pathway will be discussed in further detail. There are hidden routes for cell death as well, which are independent of APAF-1 and therefore the apoptosome. These routes are also independent of caspase-3 and 9. These hidden pathways for apoptosis are slower, but may prove useful with further research.〔Belmokhtar, C.A. et al. Apoptosome-independent Pathway for Apoptosis. Journal of Biological Chemistry 278 (2003): 29571-9580.〕 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「apoptosome」の詳細全文を読む スポンサード リンク
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