Sci. STKE, 29 August 2000
Apoptosis Dimerized DIABLO is "Smac" Dab in the Middle of Apoptosis
Apoptosis is a highly regulated process of programmed cell death (PCD). During apoptosis, Smac/DIABLO, along with cytochrome c, is released from mitochondria. Smac/DIABLO is an apoptosis-promoting protein that interferes with the ability of inhibitors of apoptosis proteins (IAPs) to block PCD. Chai et al. now uncover the mechanism by which Smac/DIABLO exerts its effects. It was previously reported that Smac/DIABLO promotes the cleavage of procaspase-3. Chai et al. demonstrated that Smac/DIABLO induced the catalytic activity of mature, cleaved caspase-3. Smac/DIABLO function depended on its ability to homodimerize; Smac/DIABLO mutants that remain monomeric did not promote caspase-3 activation. Similarly, monomeric Smac/DIABLO mutants could not bind to the BIR2 domain of X-linked IAP, suggesting that homodimerized Smac/DIABLO exerts its effects by binding certain IAPs and preventing those IAPs from blocking caspase maturation and activation. The NH2-terminus of Smac/DIABLO was shown to be crucial for blocking IAP function, and specifically, peptides consisting of the first seven NH2-terminal amino acids from Smac/DIABLO were able to promote the activation of procaspase-3 by blocking X-linked IAP function.
Chai, J., Du, C., Wu, J.-W., Kyin, S., Wang, X., and Shi, Y. (2000) Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature 406: 855-862. [Online Journal]
Citation: Dimerized DIABLO is "Smac" Dab in the Middle of Apoptosis. Sci. STKE 2000, tw6 (2000).
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882