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Requirement of Both the Second and Third BIR Domains for the Relief of X-linked Inhibitor of Apoptosis Protein (XIAP)-mediated Caspase Inhibition by Smac
Open accessAbstract
The inhibitor of apoptosis proteins (IAP) are endogenous caspase inhibitors in the metazoan and characterized by the presence of baculoviral IAP repeats (BIR). X-linked IAP (XIAP) contains three BIR domains and directly inhibits effector caspases such as caspase-7 via a linker_BIR2 fragment and initiator caspases such as caspase-9 via the BIR3 domain. A mitochondrial protein Smac/DIABLO, which is released during apoptosis, antagonizes XIAP-mediated caspase inhibition by interacting directly with XIAP. Here, using glutathione S-transferase pulldown and caspase activity assay, we show that Smac is ineffective in relieving either caspase-7 or caspase-9 inhibition by XIAP domain fragments. In addition, Smac forms a ternary complex with caspase-7 and linker_BIR2, suggesting that Smac/linker_BIR2 interaction does not sterically exclude linker_BIR2/caspase-7 interaction. However, Smac is effective in removing caspase-7 and caspase-9 inhibition by XIAP fragments containing both the BIR2 and BIR3 domains. Surface plasmon resonance measurements show that Smac interacts with the BIR2 or BIR3 domain in micromolar dissociation constants. On the other hand, Smac interacts with an XIAP construct containing both BIR2 and BIR3 domains in a subnanomolar dissociation constant by the simultaneous interaction of the Smac dimer with the BIR2 and BIR3 domains of a single XIAP molecule. This 2:1 Smac/XIAP interaction not only possesses enhanced affinity but also sterically excludes XIAP/caspase-7 interaction, demonstrating the requirement of both BIR2 and BIR3 domains for Smac to relieve XIAP-mediated caspase inhibition.
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“Upon release from mitochondria, the N-terminal amino acid alanine-valine-proline-isoeuceucine (AVPI) of Smac binds to the domain of XIAP, depriving XIAP of its ability to bind to caspase, thereby promoting apoptosis.458”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [458]
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Metadata
- Authors
- Huang, Y., Rich, R. L., Myszka, D. G., & Wu, H.
- Affiliations
- Cornell University (US)
- University of Utah (US)
- Corresponding author
- Wu, Hao
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-12
- Volume
- 278
- Issue
- 49
- Pages
- 49517-49522
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2160029849
- Cited by
- 152
- References
- 34
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 5 · 2022: 5 · 2021: 2 · 2020: 7 · 2019: 6 · 2018: 3 · 2017: 5 · 2016: 5 · 2015: 3 · 2014: 9 · 2013: 10 · 2012: 4
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (AI50872)
- 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 › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- XIAP, Smac/DIABLO, caspase inhibition, caspase-7, caspase-9, effector caspases, initiator caspases, BIR3 domain, ternary complex, apoptosis, protein-protein interaction affinity
- MeSH terms
- Carrier Proteins, Humans, Protein Binding, Proteins, Dimerization, Caspases, Mitochondrial Proteins, Intracellular Signaling Peptides and Proteins, Apoptosis Regulatory Proteins, X-Linked Inhibitor of Apoptosis Protein, Caspase Inhibitors
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