ArticleProceedings of the National Academy of Sciences of the United States of America2016
Quantitative MS-based enzymology of caspases reveals distinct protein substrate specificities, hierarchies, and cellular roles.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers.
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Who cites it
70 citing papers in PubMed, 124 citations in OpenAlex.
- SIMPATICO-Streamlined Isolation of the N-Terminome via Phosphonate Tagging and Coordination-Based Depletion.Molecular & cellular proteomics : MCP · 2026Article
- Caspase-mediated cleavage events hidden by secondary proteolysis during apoptosis.Protein science : a publication of the Protein Society · 2026Article
- Achieving protease substrate-specific inhibition by mAb dual functional selections.Protein science : a publication of the Protein Society · 2026Article
- Using a bioluminescence resonance energy transfer caspase biosensor to study caspase-3 cleavage site specificity.Bioscience reports · 2026Article
- Caspase-3/7 deficiency results in enhanced intestinal inflammation and reduced tumorigenesis.Science advances · 2026Article
- Identifying protease-activated targets and exploring therapeutic applications.Expert opinion on therapeutic targets · 2025Review
- Caspases: structural and molecular mechanisms and functions in cell death, innate immunity, and disease.Cell discovery · 2025Review
- Engineered Proteins and Chemical Tools to Probe the Cell Surface Proteome.Chemical reviews · 2025Review
- Apoptotic Caspases-3 and -7 Cleave Extracellular Domains of Membrane-Bound Proteins from MDA-MB-231 Breast Cancer Cells.International journal of molecular sciences · 2025Article
- The influence of hydrogen sulfide on gingival wound healing: An in vitro study.Journal of periodontal research · 2025Article
- N-Terminomic Identification of Intracellular MMP-2 Substrates in Cardiac Tissue.Journal of proteome research · 2024Article
- An atlas of caspase cleavage events in differentiating muscle cells.Protein science : a publication of the Protein Society · 2024Article
- Caspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia.Science advances · 2024Article
- Caspases compromise SLU7 and UPF1 stability and NMD activity during hepatocarcinogenesis.JHEP reports : innovation in hepatology · 2024Article
- Chemoproteomics Identifies State-Dependent and Proteoform-Selective Caspase-2 Inhibitors.Journal of the American Chemical Society · 2024Article
- A Comprehensive Exploration of Caspase Detection Methods: From Classical Approaches to Cutting-Edge Innovations.International journal of molecular sciences · 2024Review
- Integrating the analysis of human biopsies using post-translational modifications proteomics.Protein science : a publication of the Protein Society · 2024Review
- Application of N-Terminal Labeling Methods Provide Novel Insights into Endoproteolysis of the Prion ProteinACS chemical neuroscience · 2024Article
- In-Depth Characterization of Apoptosis N-Terminome Reveals a Link Between Caspase-3 Cleavage and Posttranslational N-Terminal Acetylation.Molecular & cellular proteomics : MCP · 2023Review
- Targeting caspase-2 interactions with tau in Alzheimer's disease and related dementias.Translational research : the journal of laboratory and clinical medicine · 2023Review
10 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Proteases constitute the largest enzyme family, yet their biological roles are obscured by our rudimentary understanding of their cellular substrates. There are 12 human caspases that play crucial roles in inflammation and cell differentiation and drive the terminal stages of cell death. Recent N-terminomics technologies have begun to enumerate the diverse substrates individual caspases can cleave in complex cell lysates. It is clear that many caspases have shared substrates; however, few data exist about the catalytic efficiencies (kcat/KM) of these substrates, which is critical to understanding their true substrate preferences. In this study, we use quantitative MS to determine the catalytic efficiencies for hundreds of natural protease substrates in cellular lysate for two understudied members: caspase-2 and caspase-6. Most substrates are new, and the cleavage rates vary up to 500-fold. We compare the cleavage rates for common substrates with those found for caspase-3, caspase-7, and caspase-8, involved in apoptosis. There is little correlation in catalytic efficiencies among the five caspases, suggesting each has a unique set of preferred substrates, and thus more specialized roles than previously understood. We synthesized peptide substrates on the basis of protein cleavage sites and found similar catalytic efficiencies between the protein and peptide substrates. These data suggest the rates of proteolysis are dominated more by local primary sequence, and less by the tertiary protein fold. Our studies highlight that global quantitative rate analysis for posttranslational modification enzymes in complex milieus for native substrates is critical to better define their functions and relative sequence of events.
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