A Dimeric Smac/Diablo Peptide Directly Relieves Caspase-3 Inhibition by XIAP

Gao, Zhonghua; Tian, Yuan; Wang, Junru; Yin, Qian; Wu, Hao; Li, Yue Ming; Jiang, Xuejun

doi:10.1074/jbc.m705258200

Cited by 99 publications

(82 citation statements)

References 48 publications

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“…A recent study utilizing a dimeric SMAC peptide further confirmed the requirement of a two-site binding mechanism for efficient derepression of XIAP-mediated inhibition of caspase-3 and -7. 30 Interestingly, when screening the dimeric human IAP survivin, we were unable to detect any peptide hits above background (data not shown), suggesting that survivin may not possess a functional IBM groove, in line with its very weak binding of IBMs. 31 Although there are many published BIR domain affinity measurements, with K D 's in the hundreds of nanomolar to micromolar range, these are almost always carried out on peptides and not full-length natural proteins.…”

Section: Discussionmentioning

confidence: 99%

The mechanism of peptide-binding specificity of IAP BIR domains

et al. 2008

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We describe the peptide-binding specificity of the baculoviral IAP repeat (BIR) domains of the human inhibitor of apoptosis (IAP) proteins, X-linked IAP, cellular IAP1 and neuronal apoptosis inhibitory protein (NAIP). Synthetic peptide libraries were used to profile each domain, and we distinguish two types of binding specificity, which we refer to as type II and type III BIR domains. Both types have a dominant selectivity for Ala in the first position of the four N-terminal residues of the peptide ligands, which constitute a core recognition motif. Our analysis allows us to define the signature of type III BIRs that demonstrate a preference for Pro in the third residue of the ligand, resembling the classic IAP-binding motif (IBM). The signature of the type II BIRs was similar to type III, but with a striking absence of specificity for Pro in the third position, suggesting that the definition of an IBM must be modified depending on the type of BIR in question. These findings explain how subtle changes in the peptide-binding groove of IAP BIR domains can significantly alter the target protein selectivity. Our analysis allows for prediction of BIR domain protein-binding preferences, provides a context for understanding the mechanism of peptide selection and heightens our knowledge of the specificity of IAP antagonists that are being developed as cancer therapeutics. Cell Death and Differentiation (2008) 15, 920-928; doi:10.1038/cdd.2008 ; published online 1 February 2008Apoptosis is a highly regulated cellular signaling pathway that results in the elimination of unwanted cells from multicellular animals. The apoptotic signaling cascades can be initiated by various extracellular (extrinsic pathway) or intracellular (intrinsic pathway) stimuli and ultimately converge on the activation of a family of proteases known as the caspasesreviewed in Fuentes-Prior and Salvesen. 1 Once active, caspases cleave a limited number of substrates that results in the destruction of the cell and its eventual disposal by phagocytic cells.Members of the inhibitor of apoptosis (IAP) protein family have the unique ability to attenuate apoptosis induced through both intrinsic and extrinsic stimuli. It is well established that the X-linked IAP (XIAP) is capable of blocking apoptosis by direct inhibition of caspase-3, -7, and -9 -reviewed in Salvesen and Duckett 2 and Eckelman et al. 3 The means by which the other members of the IAP family inhibit apoptosis is less understood. Many IAPs have the capacity to bind caspases, yet lack the ability to directly inhibit the proteolytic activity of these enzymes -reviewed in Eckelman et al. 3 The defining feature of the IAP family is the presence of 1-3 baculoviral IAP repeat (BIR) domains. BIRs are small, B70-residue zinc-coordinated domains that have been identified as the regions essential to the IAP-caspase interaction. The BIR domain(s) are necessary for the antiapoptotic activity of most IAPs. Often a surface groove on the BIR domain endows it with an affinity toward extreme N-terminal epitopes...

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Section: Discussionmentioning

confidence: 99%

The mechanism of peptide-binding specificity of IAP BIR domains

et al. 2008

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“…The combination of Fas and FasL could initiate transduction of the lethal apoptotic signal, thereby promoting cell apoptosis. High expression of the Fas protein could bind soluble FasL (Contassot et al, 2007), leading to the flotation of Fas-associated death domain protein (FADD), forming the death-inducing signaling complex (DISC), activating procaspase-8, causing the release of the upstream Caspase-8 (Iwase et al, 2006;WescheSoldato et al, 2007), subsequently activating Caspase-3, Caspase-6, and Caspase-7, which induces the chain reaction of the Caspase family (Yin and Ding, 2003;Gao et al, 2007), ultimately acting on structural proteins of cells, leading to cell apoptosis. Caspase-8 is a key enzyme acting in the upstream apoptosis pathway, and also acts as an important apoptosis initiation factor by activating almost all of the downstream Caspases in the apoptotic cascade (Fan et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Roles of Fas/Fasl, Bcl-2/Bax, and Caspase-8 in rat nonalcoholic fatty liver disease pathogenesis

Li¹,

Li²,

He³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to investigate the roles of Fas/ FasL, Bcl-2/Bax, and Caspase-8 mRNA expressions in nonalcoholic fatty liver disease (NAFLD). The apoptosis percentage was measured by flow cytometry, the immunohistochemical assay was performed for the determination of Fas, FasL, Bcl-2, and Bax expressions, and a real-time polymerase chain reaction (PCR) assay was performed to detect Caspase-8 mRNA expression. Flow cytometry showed that the apoptosis percentage of the rat liver in the experimental group increased, which increased more obviously with the extension of modeling time. Immunohistochemistry showed that with increasing hepatic steatosis, Fas and FasL protein staining intensified and the number of positive cells increased; the number of positive cells for Bcl-2 and Bax gradually increased on the 4th, 8th, and 12th weeks in the experimental group, whereas the Bcl-2/Bax ratio decreased. The real-time PCR assay showed that Caspase-8 mRNA expression increased with increasing hepatic steatosis and inflammation, exhibiting a progressively rising trend. Hepatocyte apoptosis could promote NAFLD progression; Fas, FasL, and Caspase-8 mRNA activation were important contributing factors to NAFLD. The upregulation of Bax and Bcl-2 expression might be one important mechanism of the apoptosis in NAFLD.

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“…The interaction of Smac mimetics with XIAP leads to caspase activation (18,19), while the binding of Smac mimetics to cIAP proteins enhances their E3 ligase activity, thereby promoting autoubiquitination and proteasomal degradation of cIAP proteins (20)(21)(22)(23)(24). Smac mimetic-mediated depletion of cIAP proteins leads to accumulation of NIK, activation of noncanonical NF-kB signaling, and upregulation of NF-kB target genes such as TNFa.…”

Section: Targeting Iap Proteins By Smac Mimeticsmentioning

confidence: 99%