Structural basis of IAP recognition by Smac/DIABLO

Geng Wu, Jijie Chai, Tomeka L. Suber, Jia-Wei Wu, Chunying Du, Xiaodong Wang and Yigong Shi ()
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Geng Wu: Lewis Thomas Laboratory
Jijie Chai: Lewis Thomas Laboratory
Tomeka L. Suber: 310 Aycock Dorm, University of North Carolina at Chapel Hill
Jia-Wei Wu: Lewis Thomas Laboratory
Chunying Du: University of Texas Southwestern Medical Center
Xiaodong Wang: University of Texas Southwestern Medical Center
Yigong Shi: Lewis Thomas Laboratory

Nature, 2000, vol. 408, issue 6815, 1008-1012

Abstract: Abstract Apoptosis is an essential process in the development and homeostasis of all metazoans1,2,3,4. The inhibitor-of-apoptosis (IAP) proteins suppress cell death by inhibiting the activity of caspases; this inhibition is performed by the zinc-binding BIR domains5,6 of the IAP proteins. The mitochondrial protein Smac/DIABLO promotes apoptosis by eliminating the inhibitory effect of IAPs through physical interactions7,8,9. Amino-terminal sequences in Smac/DIABLO are required for this function, as mutation of the very first amino acid leads to loss of interaction with IAPs and concomitant loss of Smac/DIABLO function9. Here we report the high-resolution crystal structure of Smac/DIABLO complexed with the third BIR domain (BIR3) of XIAP. Our results show that the N-terminal four residues (Ala-Val-Pro-Ile) in Smac/DIABLO recognize a surface groove on BIR3, with the first residue Ala binding a hydrophobic 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 Drosophila proteins Hid/Grim/Reaper. In conjunction with other observations, our results reveal how Smac may relieve IAP inhibition of caspase-9 activity. In addition to explaining a number of biological observations, our structural analysis identifies potential targets for drug screening.

Date: 2000
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DOI: 10.1038/35050012

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