Structural basis of IAP recognition by Smac/DIABLO

Apoptosis is an essential process in the development and homeostasis of all metazoans(1-4). The inhibitor-of-apoptosis (IAP) proteins suppress cell de ath by inhibiting the activity of caspases; this inhibition is performed by the zinc-binding BIR domains(5,6) of the IAP proteins. The mitochondrial p rotein Smac/DIABLO promotes apoptosis by eliminating the inhibitory effect of IAPs through physical interactions(7-9). Amino-terminal sequences in Sma c/DIABLO are required for this function, as mutation of the very first amin o acid leads to loss of interaction with IAPs and concomitant loss of Smac/ DIABLO function(9). Here we report the high-resolution crystal structure of Smac/DIABLO complexed with the third BIR domain (BIR3) of XIAP. Our result s show that the N-terminal four residues (Ala-Val-Pro-Ile) in Smac/DIABLO r ecognize a surface groove on BIR3, with the first residue Ala binding a hyd rophobic pocket and making five hydrogen bonds to neighbouring residues on BIR3. These observations provide a structural explanation for the roles of the Smac N terminus as well as the conserved N-terminal sequences in the Dr osophila proteins Hid/Grim/Reaper. In conjunction with other observations, our results reveal how Smac may relieve IAP inhibition of caspase-9 activit y. In addition to explaining a number of biological observations, our struc tural analysis identifies potential targets for drug screening.