XIAP inhibits caspase‐3 and ‐7 using two binding sites: evolutionarily conserved mechanism of IAPs
Fiona L. Scott,Jean-Bernard Denault,Stefan J. Riedl,Hwain Shin,Martin Renatus,Guy S. Salvesen +5 more
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TLDR
It is shown that the BIR2 domain contributes substantially to inhibition of executioner caspases, and it is predicted that the origin of the death stimulus should dictate the efficiency of inhibition by XIAP.Abstract:
The X-linked inhibitor of apoptosis protein (XIAP) uses its second baculovirus IAP repeat domain (BIR2) to inhibit the apoptotic executioner caspase-3 and -7. Structural studies have demonstrated that it is not the BIR2 domain itself but a segment N-terminal to it that directly targets the activity of these caspases. These studies failed to demonstrate a role of the BIR2 domain in inhibition. We used site-directed mutagenesis of BIR2 and its linker to determine the mechanism of executioner caspase inhibition by XIAP. We show that the BIR2 domain contributes substantially to inhibition of executioner caspases. A surface groove on BIR2, which also binds to Smac/DIABLO, interacts with a neoepitope generated at the N-terminus of the caspase small subunit following activation. Therefore, BIR2 uses a two-site interaction mechanism to achieve high specificity and potency for inhibition. Moreover, for caspase-7, the precise location of the activating cleavage is critical for subsequent inhibition. Since apical caspases utilize this cleavage site differently, we predict that the origin of the death stimulus should dictate the efficiency of inhibition by XIAP.read more
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Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family
TL;DR: Current knowledge of the caspase‐inhibitory potential of the human IAPs is reviewed and it is shown that XIAP is probably the only bona fide casp enzyme inhibitor, suggesting that the other family members never gained the ability to directly inhibit caspases activity.
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IAPs: from caspase inhibitors to modulators of NF-κB, inflammation and cancer
Mads Gyrd-Hansen,Pascal Meier +1 more
TL;DR: Recent studies indicate that IAPs not only regulate caspases and apoptosis, but also modulate inflammatory signalling and immunity, mitogenic kinase signalling, proliferation and mitosis, as well as cell invasion and metastasis.
Journal ArticleDOI
Targeting IAP proteins for therapeutic intervention in cancer
Simone Fulda,Domagoj Vucic +1 more
TL;DR: The most widely used approach is based on mimicking the IAP-binding motif of second mitochondria-derived activator of caspase (SMAC), which functions as an endogenous IAP antagonist.
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IAPs, RINGs and ubiquitylation
David L. Vaux,John Silke +1 more
TL;DR: The inhibitor of apoptosis (IAP) proteins all contain one or more baculoviral IAP repeat motifs, through which they interact with various other proteins, and the IAPs themselves are controlled by ubiquitin-mediated degradation.
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The inhibitors of apoptosis (IAPs) as cancer targets.
TL;DR: This review addresses IAP proteins as therapeutic targets for the treatment of cancer and emphasizes the importance of novel therapeutic approaches for cancer therapy.
References
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Journal ArticleDOI
Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition.
TL;DR: The identification of a novel protein, Smac, which promotes caspase activation in the cytochrome c/Apaf-1/caspase-9 pathway and increases cells' sensitivity to apoptotic stimuli is reported.
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Identification of DIABLO, a Mammalian Protein that Promotes Apoptosis by Binding to and Antagonizing IAP Proteins
Anne M. Verhagen,Paul G Ekert,Paul G Ekert,Miha Pakusch,John Silke,Lisa M. Connolly,Gavin E. Reid,Robert L. Moritz,Richard J. Simpson,David L. Vaux +9 more
TL;DR: DIABLO (direct IAP binding protein with low pI) is a novel protein that can bind MIHA and can also interact with MIHB and MIHC and the baculoviral IAP, OpIAP.
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X-linked IAP is a direct inhibitor of cell-death proteases
TL;DR: It is shown that human X-chromosome-linked IAP directly inhibits at least two members of the caspase family of cell-death proteases, caspasing-3 and caspases-7, providing evidence for a mechanism of action for these mammalian cell- death suppressors.
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IAP proteins: blocking the road to death's door
Guy S. Salvesen,Colin S. Duckett +1 more
TL;DR: The functional and structural properties of the IAP gene family, a group of structurally related proteins that, in addition to their ability to suppress apoptotic cell death, are involved in an increasing number of seemingly unrelated cellular functions, are reviewed.
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Caspase structure, proteolytic substrates, and function during apoptotic cell death.
TL;DR: These enzymes define a new class of cysteine proteases and comprise a multi-gene family with more than a dozen distinct mammalian family members that account for the majority of cellular and morphological events that occur during cell death.