Cited by 864Cell death mechanisms and regulationUbiquitin and proteasome pathwaysCancer-related Molecular Pathways

Structural and biochemical basis of apoptotic activation by Smac/DIABLO

Chai, Jijie, Du, Chunying, Wu, Jia-Wei, Kyin, Saw, Wang, Xiaodong, Shi, Yigong·2000·Nature

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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Crossref · 10.1038/35022514

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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”

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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
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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