DIABLO

DIABLO Background

Direct inhibitor of apoptosis-binding protein with a low isoelectric point, pI (DIABLO), also known as a second mitochondria-derived activator of caspase (SMAC), is a pro-apoptotic mitochondrial protein. DIABLO/SMAC is normally localized within the mitochondria ^[1]. It has an N-terminus with a stretch of amino acids characteristic of mitochondrial targeting sequences that are removed from proteins upon import into mitochondria. Following an apoptotic trigger, mitochondria undergo loss of inner mitochondrial membrane potential and subsequent mitochondrial membrane permeabilization (MMP) ^[2]. The N-terminally processed DIABLO/SMAC is released into the cytosol together with cytochrome c ^[1][2]. Cytochrome c directly activates the Apaf-1/caspase-9 apoptosome and downstream effector caspases, leading to apoptosis ^[3]. However, the activity of mature caspases is inhibited by their interaction with the inhibitor of apoptosis proteins (IAPs) ^[4][5]. DIABLO/SMAC promotes apoptosis by abrogating the inhibitory effect of IAPs through physical interactions ^[6]. Amino-terminal sequences in DIABLO/SMAC are required for its interaction with IAPs ^[7][8]. Studies demonstrated that DIABLO/SMAC interacts with the BIR2 and BIR3 domains of XIAP, allowing the release of caspase-3 ^[9] and caspase 9 ^[10], respectively. Several studies have shown that overexpression of DIABLO/SMAC sensitizes tumor cells to apoptosis ^[11][12]. The role of DIABLO/SMAC, therefore, may have significant diagnostic and therapeutic features in carcinogenesis. Furthermore, amino-terminal DIABLO/SMAC derivatives and small molecules that mimic the DIABLO/SMAC function could be a potential therapy for tumors with the expression of IAPs.

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[7] Verhagen, A. M. et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102, 43?3 (2000).
[8] Chai, J. et al. Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature 406, 855-62 (2000).
[9] Gao Z, Tian Y, Wang J, Yin Q, Wu H, Li YM, Jiang X: A dimeric Smac/diablo peptide directly relieves caspase-3 inhibition by XIAP. Dynamic and cooperative regulation of XIAP by Smac/Diablo. J Biol Chem. 2007, 282 (42): 30718-30727.
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