Structural and biochemical basis of apoptotic activation by Smac/DIABLO
Abstract
Apoptosis (programmed cell death), an essential process in the development and homeostasis of metazoans, is carried out by caspases. The mitochondrial protein Smac/DIABLO performs a critical function in apoptosis by eliminating the inhibitory effect of IAPs (inhibitor of apoptosis proteins) on caspases. Here we show that Smac/DIABLO promotes not only the proteolytic activation of procaspase-3 but also the enzymatic activity of mature caspase-3, both of which depend upon its ability to interact physically with IAPs. The crystal structure of Smac/DIABLO at 2.2 A resolution reveals that it homodimerizes through an extensive hydrophobic interface. Missense mutations inactivating this dimeric interface significantly compromise the function of Smac/DIABLO. As in the Drosophila proteins Reaper, Grim and Hid, the amino-terminal amino acids of Smac/DIABLO are indispensable for its function, and a seven-residue peptide derived from the amino terminus promotes procaspase-3 activation in vitro. These results establish an evolutionarily conserved structural and biochemical basis for the activation of apoptosis by Smac/DIABLO.
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MOMP directly promotes the cytosolic release of apoptogenic factors that normally reside in the mitochondrial intermembrane space, including cytochrome c (CYCS) and SMAC.
“MOMP directly promotes the cytosolic release of apoptogenic factors that normally reside in the mitochondrial intermembrane space [40, 44, 156]. These mitochondrial proteins include (but are not limited to) cytochrome c, somatic (CYCS), which usually operates as an electron shuttle in the mitochondrial respiratory chain [157–160], and diablo IAP-binding mitochondrial protein (DIABLO; also known as”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [161]
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- Authors
- Chai, J., Du, C., Wu, J.-W., Kyin, S., Wang, X., & Shi, Y.
- Affiliations
- Princeton University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Shi, Yigong
- Venue
- Nature
- Published
- 2000-08
- Volume
- 406
- Issue
- 6798
- Pages
- 855-862
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2123513769
- Cited by
- 864
- References
- 37
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 18 · 2023: 27 · 2022: 18 · 2021: 20 · 2020: 18 · 2019: 12 · 2018: 15 · 2017: 22 · 2016: 25 · 2015: 29 · 2014: 34 · 2013: 42 · 2012: 33
- FWCI
- 23.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- Smac/DIABLO, apoptosis, caspase-3 activation, inhibitor of apoptosis proteins, homodimerization, hydrophobic interface, reaper, Grim, hid, Drosophila, missense mutations, amino-terminal peptide, programmed cell death
- MeSH terms
- Amino Acid Sequence, Carrier Proteins, Enzyme Activation, Enzyme Precursors, Escherichia coli, Models, Chemical, Molecular Sequence Data, Protein Conformation, Mutagenesis, Site-Directed, Apoptosis, Crystallography, X-Ray, Dimerization, Caspases, Mitochondrial Proteins, Intracellular Signaling Peptides and Proteins, Apoptosis Regulatory Proteins, Caspase 3
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