XIAP/Smac

The natural inhibitor of IAPs, Smac (also called DIABLO) [243, 244] blocks IAP binding of caspases. NMR and X-ray structures of the XIAP/Smac complex showed that the first four residues (AVPI) of the N-terminal domain of Smac bind to the same surface groove on XIAP BIR3 that recognizes the N-terminus of caspase-9 (Fig. 10) [245-247]. The terminal alanine methyl group fits into a small pocket,... 

There is also crosstalk between the two pathways above the mitochondria. The BH3-only protein BID is cleaved by caspase-8 and -10 which yields truncated BID (tBED), the active pro-apoptotic fragment of BID. Thereby, even in cells in which the direct apoptosis pathway which result from death receptor crosslinking is blocked, e.g. by high expression levels ofthex-linked IAP (XIAP), the activity of tBED on mitochondria can result in the activation of caspase-3 because the IAP-imposed block on full caspase-3 activation and caspase-9 activity at the apoptosome is released by Smac/ DIABLO. 

MacFarlane, M., et al., Proteasome-mediated Degradation of Smac during Apoptosis XIAP Promotes Smac Ubiquitination in Vitro. J Biol Chem,... 

Danial NN, Korsmeyer SJ (2004) CeU death critical control points. CeU 116 205-219 Denault JB, Eckelman BP, Shin H, Pop C, Salvesen GS (2007) Caspase-3 attenuates XIAP-mediated inhibition of caspase-9. Biochem J 405(1) 11-19 Deng Y, Lin Y, Wu X (2002) TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/DIABLO. Genes Dev 16 33-45... 

Liu Z, Sun C, Olejniczak ET, Meadows RP, Betz SF, Dost T, Herrmann J, Wu JC, Fesik SW (2000) Structural basis for binding of Smac/DIABLO to the XIAP B1R3 domain. Nature 408 1004-1008... 

Figure 4 Structures of small molecule inhibitors of (a, b) CDK, (c) HSP90, (d) survivin gene expression, (e-l) XIAP, and (m) omi/HtrA2. (a) flavopiridol, (b) purvalanol, (c) 5-aminoimidazole-4-carboxamide-1 -beta-D-ribofuranoside (AlCAR), (d) YM155, (e-h) SMAC-mimetics, (i) Smac mimetic tetrazoyl thioether, (j) benzoquinone embelin, (k) aryl sulfonamide, (I) XIAP inhibitor of Polyphenylurea series, (m) Omi/HtrA2 inhibitor Ucf-101.

The broad-spectrum peptidomimetic lAP family inhibitors were also recently developed (107). Designed based on (7, 5)-bicyclic scaffold, these SMAC-mimetics were found to antagonize the protein interactions that involve XIAP, melanoma... 

Huang Y, et al. Requirement of both the second and third BIR domains for the relief of X-linked inhibitor of apoptosis protein 120. (XIAP)-mediated caspase inhibition by Smac. J. Biol. Chem. 2003 278 49517-49522. 

Significantly, interactions between Smac and the B1R3 domain of XIAP are localized to the four N-terminal residues of... 

Arnt CR, Chiorean MV, Heldebrant MP, Gores GJ, Kaufmann SH. Synthetic Smac/DIABLO peptides enhance the effects of chemotherapeutic agents by binding XIAP and clAPl in situ. J. Biol. Chem. 2002 277 44236-44243. 

Members of the lAP family inhibit caspases 3, 7 and 9 and interact with inhibitory Smac/DIABLO protein that is released from the mitochondria during apoptosis. They are over-expressed in some cancers. Peptide inhibitors of lAPs were then designed based on the Smac/DIABLO protein. The N-terminal sequence (AVPI) of Smac/DIABLO reacts with BIR3 of X-linked lAP (XIAP) and its N-terminal heptapetide promote procaspase-3 activation [241]. The... 

Bratton SB, Cohen GM. Death receptors leave a caspase footprint that Smacs of XIAP. Cell Death Differ 2003 10(l) 4-6. 

Srinivasula SM, Hegde R, Saleh A et al (2001) A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis. Nature 410 112-116... 

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