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The Human Anti-apoptotic Proteins cIAP1 and cIAP2 Bind but Do Not Inhibit Caspases
Open accessAbstract
cIAPs (cellular inhibitor of apoptosis proteins) 1 and 2 are able to regulate apoptosis when ectopically expressed in recipient cells and probably also in vivo. Previous work suggested that this is at least partially due to direct caspase inhibition, mediated by two of the three baculovirus IAP repeat (BIR) domains that are contained in these proteins. In support of this we show that the BIR domains 2 and 3 of the two cIAPs are able to bind caspases-7 and -9. However, we demonstrate that neither of these BIR domains is able to inhibit caspases because of critical substitutions in the regions that target caspase inhibition in the X-linked IAP, a tight binding caspase inhibitor. The cIAP BIR domains can be converted to tight binding caspase inhibitors by substituting these critical residues with XIAP residues. Thus, cIAPs maintain protein scaffolds suitable for direct caspase inhibition but have lost or never acquired specific caspase inhibitory interaction sites. Consequently, although the binding function of the cIAP BIRs may be important for their physiologic function, caspase inhibition is not.
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“XIAP is the only IAP protein family member that counteracts the apoptotic cascade by stably binding to and hence physically blocking caspases [184, 185].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [184]
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Metadata
- Authors
- Eckelman, B. P., & Salvesen, G. S.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Salvesen, Guy S.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-02
- Volume
- 281
- Issue
- 6
- Pages
- 3254-3260
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2148894303
- Cited by
- 391
- References
- 45
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 9 · 2023: 9 · 2022: 9 · 2021: 25 · 2020: 13 · 2019: 17 · 2018: 20 · 2017: 10 · 2016: 19 · 2015: 24 · 2014: 27 · 2013: 22 · 2012: 24
- FWCI
- 9.79
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG15402, R01AG015402)
- National Cancer Institute (2T32CA77109, T32CA077109)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- cIAP1, cIAP2, caspase inhibition, caspase-7, caspase-9, XIAP, protein-protein binding, apoptosis regulation
- MeSH terms
- Amino Acid Sequence, Cell Line, Enzyme Inhibitors, Escherichia coli, Humans, Kinetics, Molecular Sequence Data, Protein Binding, Recombinant Proteins, Immunoblotting, Apoptosis, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Caspases, Inhibitor of Apoptosis Proteins, X-Linked Inhibitor of Apoptosis Protein, Caspase 3, Caspase 7, Caspase 9, Caspase Inhibitors
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