ArticleProceedings of the National Academy of Sciences of the United States of America2023
Activation of caspase-9 on the apoptosome as studied by methyl-TROSY NMR.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 25 citations in OpenAlex.
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- Comprehensive Pan-Cancer Analysis of TRNT1 as a Potential Biomarker for Breast Cancer.Journal of cellular and molecular medicine · 2025Article
- Cell death signaling and immune regulation: new perspectives on targeted therapy for sepsis.Cellular & molecular biology letters · 2025Review
- Biological insights from integrative modeling of intrinsically disordered protein systems.Current opinion in structural biology · 2025Review
- A histidine switch regulates pH-dependent filament formation by the caspase-9 CARD.bioRxiv : the preprint server for biology · 2025Article
- NADInternational journal of molecular sciences · 2025Article
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- The Dual Role of the TRAIL-DR5 Signaling Axis in Cardiovascular Disease: From Molecular Mechanisms to Targeted Therapies.Biologics : targets & therapy · 2025Review
- An NMR sample preparation case study: Considerations for the self-destructive protease caspase-6.PloS one · 2025Article
- Programmed cell death: molecular mechanisms, biological functions, diseases, and therapeutic targets.MedComm · 2024Review
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Mitochondrial apoptotic signaling cascades lead to the formation of the apoptosome, a 1.1-MDa heptameric protein scaffold that recruits and activates the caspase-9 protease. Once activated, caspase-9 cleaves and activates downstream effector caspases, triggering the onset of cell death through caspase-mediated proteolysis of cellular proteins. Failure to activate caspase-9 enables the evasion of programmed cell death, which occurs in various forms of cancer. Despite the critical apoptotic function of caspase-9, the structural mechanism by which it is activated on the apoptosome has remained elusive. Here, we used a combination of methyl-transverse relaxation-optimized NMR spectroscopy, protein engineering, and biochemical assays to study the activation of caspase-9 bound to the apoptosome. In the absence of peptide substrate, we observed that both caspase-9 and its isolated protease domain (PD) only very weakly dimerize with dissociation constants in the millimolar range. Methyl-NMR spectra of isotope-labeled caspase-9, within the 1.3-MDa native apoptosome complex or an engineered 480-kDa apoptosome mimic, reveal that the caspase-9 PD remains monomeric after recruitment to the scaffold. Binding to the apoptosome, therefore, organizes caspase-9 PDs so that they can rapidly and extensively dimerize only when substrate is present, providing an important layer in the regulation of caspase-9 activation. Our work highlights the unique role of NMR spectroscopy to structurally characterize protein domains that are flexibly tethered to large scaffolds, even in cases where the molecular targets are in excess of 1 MDa, as in the present example.
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