Structures of BIRC6-client complexes provide a mechanism of SMAC-mediated release of caspases
Open accessPublished version of a preprint
Abstract
Tight regulation of apoptosis is essential for metazoan development and prevents diseases such as cancer and neurodegeneration. Caspase activation is central to apoptosis, and inhibitor of apoptosis proteins (IAPs) are the principal actors that restrain caspase activity and are therefore attractive therapeutic targets. IAPs, in turn, are regulated by mitochondria-derived proapoptotic factors such as SMAC and HTRA2. Through a series of cryo–electron microscopy structures of full-length human baculoviral IAP repeat–containing protein 6 (BIRC6) bound to SMAC, caspases, and HTRA2, we provide a molecular understanding for BIRC6-mediated caspase inhibition and its release by SMAC. The architecture of BIRC6, together with near-irreversible binding of SMAC, elucidates how the IAP inhibitor SMAC can effectively control a processive ubiquitin ligase to respond to apoptotic stimuli.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins
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- Authors
- Hunkeler, M., Jin, C. Y., & Fischer, E. S.
- Affiliations
- Harvard University (US)
- Corresponding author
- Fischer, Eric S.
- Venue
- Science
- Published
- 2023-03-17
- Volume
- 379
- Issue
- 6637
- Pages
- 1105-1111
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W4319662839
- Cited by
- 48
- References
- 4
- Citations by year
- 2026: 16 · 2025: 13 · 2024: 15 · 2023: 4
- FWCI
- 4.26
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Science (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (P01CA066996)
- 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
- BIRC6, Smac/DIABLO, caspase inhibition, inhibitor of apoptosis proteins, HtrA2, ubiquitin ligase, apoptosis regulation, protein complex structure
- MeSH terms
- Protein Domains, High-Temperature Requirement A Serine Peptidase 2, Animals, Enzyme Activation, Humans, Apoptosis, Caspases, Cryoelectron Microscopy, Mitochondrial Proteins, Apoptosis Regulatory Proteins, Inhibitor of Apoptosis Proteins
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