Affinage

CASP7

Caspase-7 · UniProt P55210

Length
303 aa
Mass
34.3 kDa
Annotated
2026-06-09
47 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/5 claims corpus-supported (80%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CASP7 (Mch3/ICE-LAP3/CMH-1) is an executioner cysteine protease that functions as an effector node in the apoptotic caspase cascade, cleaving downstream death substrates once activated by upstream proteolytic signals (PMID:8521391, PMID:9078237). It is synthesized as a ~35-kDa cytoplasmic zymogen that is converted to the active large/small (p20/p12) heterodimer by cleavage at Asp198-Ser199, while autocatalytic removal of the pro-sequence at Asp23-Ala24 is dispensable for activity (PMID:8521391, PMID:8576161, PMID:8631895). Activation is driven by multiple upstream proteases: CASP3/CPP32 efficiently cleaves proCASP7 (but not the reverse, establishing CASP7 as downstream of CASP3), CASP8/Mch4 cleaves proCASP7 at a conserved IXXD-S site, and granzyme B processes CASP7 at Asp198-Ser199 during cytotoxic-lymphocyte-mediated killing (PMID:8521391, PMID:8755496, PMID:8805307, PMID:8631895). Endogenous CASP7 is processed upon Fas or TNF death stimuli and during wild-type p53-induced apoptosis, coincident with cleavage of its substrates PARP and lamin B1 (PMID:8576161, PMID:9078237). Active CASP7 is restrained by XIAP, which binds via its linker-BIR2 domain; a small molecule engaging CASP7 at Asp93 releases this inhibition and selectively kills CASP3-deficient cancer cells, defining the XIAP:CASP7 interface as a druggable apoptotic node (PMID:40533441).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 1995 High

    Established that CASP7 is an intrinsically active executioner protease whose mature form is a p20/p12 heterodimer and whose in vivo activation depends in part on CASP3.

    Evidence Bacterially expressed recombinant Mch3, in vitro PARP cleavage assay, subunit reconstitution with CPP32, and Sf9 apoptosis induction

    PMID:8521391

    Open questions at the time
    • Did not establish the physiological upstream trigger in human cells
    • Relative contributions of autoactivation versus CASP3-driven activation not quantified in vivo
  2. 1996 High

    Defined the upstream activators of CASP7, placing it as a downstream substrate of the apical/initiator protease CASP8/Mch4 and of granzyme B at a conserved IXXD-S cleavage motif.

    Evidence In vitro cleavage assays with bacterially expressed proMch3, CASP8 and granzyme B; DEVD-CHO inhibition

    PMID:8755496

    Open questions at the time
    • In vitro reconstitution only; cellular ordering of CASP8 vs CASP3 input not resolved
  3. 1996 Medium

    Localized the CASP7 zymogen to the cytoplasm and demonstrated physiological activation, showing pro-domain-deleted CASP7 is pro-apoptotic and endogenous protein is processed upon death-receptor signaling.

    Evidence Subcellular fractionation, overexpression in MCF7 cells, western blot of processed subunits after Fas/TNF stimulation

    PMID:8576161

    Open questions at the time
    • Single fractionation method for localization
    • Did not identify which upstream caspase mediates Fas/TNF-induced processing
  4. 1996 High

    Mapped the precise activating cleavage site (Asp198-Ser199 between p20 and p12) and showed granzyme B activates endogenous CASP7 in cytotoxic-lymphocyte killing, while pro-sequence removal is not required for activity.

    Evidence In vitro cleavage with recombinant CMH-1 and granzyme B, N-terminal sequencing, activity assays, and granzyme B/perforin treatment of Jurkat cells

    PMID:8631895 PMID:8805307

    Open questions at the time
    • Granzyme B cleavage of endogenous CASP7 within intact target cells inferred from processing, not direct enzymology in situ
  5. 1997 Medium

    Integrated CASP7 into the p53-dependent intrinsic apoptotic pathway, showing it is activated alongside CASP3 with coincident PARP and lamin B1 cleavage.

    Evidence Temperature-sensitive p53 LTR6 cell line, western blot for caspase processing and substrate cleavage

    PMID:9078237

    Open questions at the time
    • Epistasis between CASP3 and CASP7 not dissected
    • Single-lab correlative timing rather than loss-of-function proof
  6. 2025 High

    Identified XIAP linker-BIR2 binding as the physiological brake on active CASP7 and defined Asp93 as a druggable site whose engagement releases inhibition and selectively kills CASP3-deficient cancer cells.

    Evidence Virtual screening, in vitro binding, D93 site-directed mutagenesis, caspase activity and viability assays in CASP3/DR lines, and in vivo xenograft

    PMID:40533441

    Open questions at the time
    • Structural detail of the XIAP:CASP7 interface not fully resolved
    • Selectivity over other caspases of the small molecule not exhaustively defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The full endogenous substrate repertoire of CASP7 beyond PARP and lamin B1, and its non-redundant role relative to CASP3 in tissue-level apoptosis, remain unresolved in the available corpus.
  • No proteome-wide substrate map in the timeline
  • Functional distinction from CASP3 not established by loss-of-function genetics

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016787 hydrolase activity 2
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-5357801 Programmed Cell Death 3 R-HSA-168256 Immune System 1
Partners
CASP3CASP8XIAP

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 Recombinant Mch3 (CASP7) alpha has intrinsic autocatalytic/autoactivation activity and cleaves PARP with specificity similar to CPP32. The active form is a heterodimer of large (p20) and small (p12) subunits derived from a precursor. CPP32-p17 subunit can form an active heteromeric enzyme complex with Mch3 alpha-p12 subunit, and CPP32 can efficiently cleave proMch3 alpha (but not the reverse), suggesting Mch3 alpha activation in vivo depends in part on CPP32 activity. Bacterially expressed recombinant protein, in vitro protease assay, Sf9 cell apoptosis induction, subunit reconstitution Cancer research High 8521391
1996 Mch4 (CASP8) cleaves recombinant proMch3 (proCASP7) at a conserved IXXD-S sequence to produce the large and small subunits of the active protease. Granzyme B also cleaves proMch3 at this site. This positions CASP7 as a downstream substrate in the apoptotic caspase cascade activated by Mch4. In vitro cleavage assay using bacterially expressed proteins, E. coli expression, DEVD-CHO inhibition Proceedings of the National Academy of Sciences of the United States of America High 8755496
1996 ICE-LAP3 (CASP7) pro-enzyme is a 35-kDa cytoplasmic protein. Overexpression of a truncated (pro-domain deleted) ICE-LAP3 induces apoptosis in MCF7 cells. Endogenous ICE-LAP3 is processed to its subunit forms upon receipt of a Fas or TNF death stimulus, demonstrating physiological activation during apoptosis. Subcellular fractionation, overexpression in MCF7 cells, western blot detection of processed subunits after Fas/TNF stimulation The Journal of biological chemistry Medium 8576161
1996 Granzyme B activates ICE-LAP3/Mch3/CASP7 in CTL-mediated killing. Granzyme B processes endogenous ICE-LAP3 in Jurkat T cells treated with granzyme B and sublytic perforin, preceding apoptosis. This places CASP7 as a direct downstream target of granzyme B in the cytotoxic lymphocyte death pathway. In vitro granzyme B treatment of Jurkat cells with perforin, western blot of endogenous CASP7 processing, apoptosis assay Current biology : CB High 8631895 8805307
1996 Granzyme B specifically cleaves CMH-1 (CASP7) at Asp198-Ser199 between the p20 and p12 subunits to activate the cysteine protease. Autocatalytic cleavage between p20 and the pro-sequence at Asp23-Ala24 is not required for CMH-1 activity in vitro. In vitro cleavage assay with recombinant CMH-1 and granzyme B, N-terminal sequencing to map cleavage sites, activity assay The Journal of biological chemistry High 8631895
1997 CPP32 (CASP3) and Mch3 alpha (CASP7) are both processed and activated during wild-type p53-induced apoptosis in LTR6 cells, coinciding with cleavage of PARP and lamin B1, placing CASP7 as an effector caspase in the p53-dependent apoptotic pathway. Temperature-sensitive p53 cell line (LTR6), western blot for caspase processing and substrate cleavage (PARP, lamin B1) The Biochemical journal Medium 9078237
2025 XIAP binds CASP7 via its linker-BIR2 domain to inhibit active CASP7. A small molecule (643943) binds to CASP7 at Asp93, releases the XIAP linker-BIR2 domain, and activates CASP7, selectively killing CASP3-deficient (CASP3/DR) cancer cells. Mutation of Asp93 on CASP7 or removal of the hydroxyl group on 643943 abolished cytotoxicity, defining the binding interface. Virtual screening, in vitro binding assays, site-directed mutagenesis (D93 substitution), caspase activity assay, cell viability assay in MCF7 and other CASP3/DR lines, in vivo xenograft Cell death & disease High 40533441

Source papers

Stage 0 corpus · 47 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains. Proceedings of the National Academy of Sciences of the United States of America 672 8755496
1995 Mch3, a novel human apoptotic cysteine protease highly related to CPP32. Cancer research 380 8521391
2007 Template-based modeling and free modeling by I-TASSER in CASP7. Proteins 338 17894355
1996 ICE-LAP3, a novel mammalian homologue of the Caenorhabditis elegans cell death protein Ced-3 is activated during Fas- and tumor necrosis factor-induced apoptosis. The Journal of biological chemistry 329 8576161
2007 Structure prediction for CASP7 targets using extensive all-atom refinement with Rosetta@home. Proteins 119 17894356
2007 Assessment of CASP7 predictions for template-based modeling targets. Proteins 118 17894352
1996 Cytotoxic T-cell-derived granzyme B activates the apoptotic protease ICE-LAP3. Current biology : CB 91 8805307
2007 Assessment of disorder predictions in CASP7. Proteins 83 17680688
2007 Automated server predictions in CASP7. Proteins 81 17894354
2007 Assessment of CASP7 structure predictions for template free targets. Proteins 75 17894330
2007 Prediction of global and local model quality in CASP7 using Pcons and ProQ. Proteins 68 17894353
1996 Processing and activation of CMH-1 by granzyme B. The Journal of biological chemistry 58 8631895
2007 Assessment of intramolecular contact predictions for CASP7. Proteins 55 17671976
2007 Analysis of TASSER-based CASP7 protein structure prediction results. Proteins 48 17705276
2007 Assessment of predictions submitted for the CASP7 function prediction category. Proteins 41 17654548
2019 A rare missense variant of CASP7 is associated with familial late-onset Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association 36 30503768
1997 Identification and mapping of Casp7, a cysteine protease resembling CPP32 beta, interleukin-1 beta converting enzyme, and CED-3. Genomics 35 9070923
2007 Assessment of predictions submitted for the CASP7 domain prediction category. Proteins 34 17680686
2007 Evaluation of 3D-Jury on CASP7 models. BMC bioinformatics 26 17711571
2015 Genome-wide haplotype association study identify TNFRSF1A, CASP7, LRP1B, CDH1 and TG genes associated with Alzheimer's disease in Caribbean Hispanic individuals. Oncotarget 24 26621834
1997 Activation of CPP32 and Mch3 alpha in wild-type p53-induced apoptosis. The Biochemical journal 24 9078237
2018 Detection of Plasmid-Mediated β-Lactamase Genes and Emergence of a Novel AmpC (CMH-1) in Enterobacter cloacae at a Medical Center in Southern Taiwan. Journal of clinical medicine 23 30577544
2016 A loss of function variant in CASP7 protects against Alzheimer's disease in homozygous APOE ε4 allele carriers. BMC genomics 22 27358062
1996 Chromosomal localization of the human genes, CPP32, Mch2, Mch3, and Ich-1, involved in cellular apoptosis. Biochemical and biophysical research communications 22 8780721
2013 HuGE systematic review and meta-analysis demonstrate association of CASP-3 and CASP-7 genetic polymorphisms with cancer risk. Genetics and molecular research : GMR 20 23765963
1998 Cloning, sequencing, and expression of an endoglucanase gene from the rumen anaerobic fungus Neocallimastix frontalis MCH3. Bioscience, biotechnology, and biochemistry 20 9805384
1995 Effects of live Saccharomyces cerevisiae cells on zoospore germination, growth, and cellulolytic activity of the rumen anaerobic fungus, Neocallimastix frontalis MCH3. Current microbiology 20 7549764
2007 Domain definition and target classification for CASP7. Proteins 18 17654725
2017 Genetic Susceptibility in Acute Pancreatitis: Genotyping of GSTM1, GSTT1, GSTP1, CASP7, CASP8, CASP9, CASP10, LTA, TNFRSF1B, and TP53 Gene Variants. Pancreas 14 27984487
2015 CASP7 variants modify susceptibility to cervical cancer in Chinese women. Scientific reports 13 25784056
2013 Potentially functional polymorphisms in the CASP7 gene contribute to gastric adenocarcinoma susceptibility in an eastern Chinese population. PloS one 11 24040159
2012 Association between CASP7 and CASP14 genetic polymorphisms and the risk of childhood leukemia. Human immunology 11 22548721
2008 Genetic and expression analysis of CASP7 gene in a European Caucasian population with rheumatoid arthritis. The Journal of rheumatology 10 18785314
2019 Association of genetic polymorphisms in CASP7 with risk of ischaemic stroke. Scientific reports 7 31819117
2012 Association of CASP7 polymorphisms and survival of patients with non-small cell lung cancer with platinum-based chemotherapy treatment. Chest 7 22441531
1996 Chromosomal mapping of cell death proteases CPP32, MCH2, and MCH3. Genomics 7 8812467
2023 lncfos/miR-212-5p/CASP7 Axis-Regulated miR-212-5p Protects the Brain Against Ischemic Damage. Molecular neurobiology 6 36715920
2020 The Relevance of SNPs at 3'UTR Region of CASP7 and miR-371b-5p Associated Diseases: A Computational Analysis. Cell biochemistry and biophysics 6 32951155
2023 TLR2 and CASP7 as the biomarkers associated with non-alcoholic fatty liver disease and chronic kidney disease. Biochemical and biophysical research communications 5 37209562
2021 Role of CASP7 polymorphisms in noise-induced hearing loss risk in Han Chinese population. Scientific reports 5 33469117
2024 The Nephroprotective Activity of Boesenbergia Rotunda Rhizome by Reducing Creatinine, Urea Nitrogen, Glutamic Pyruvic Transaminase, and Malondialdehyde Levels in the Blood and Attenuating the Expression of Havcr1 (KIM-1), Lcn2 (NGAL), Casp3, and Casp7 Genes in the Kidney Cortex of Cisplatin-Induced Sprague-Dawley Rats. Journal of experimental pharmacology 4 38736464
2011 Unsupervised Integration of Multiple Protein Disorder Predictors: The Method and Evaluation on CASP7, CASP8 and CASP9 Data. Proteome science 3 22166115
2025 Blocking XIAP:CASP7-p19 selectively induces apoptosis of CASP3/DR malignancies by a novel reversible small molecule. Cell death & disease 2 40533441
2019 [Expression of Cell Cycle, Oxidative Stress, and Apoptosis Related Genes Chek1, Hmox1, Casp7 in Rat Liver Exposed to Carbon Tetrachloride]. Molekuliarnaia biologiia 2 30895955
2026 Fufang Baizhi tincture protects melanocytes from oxidative stress by targeting CASP7-mediated apoptosis and EP300-associated transcriptional regulation. Journal of ethnopharmacology 0 41713816
2025 The complete genome sequence of the Pediococcus siamensis type strain MCH3-2T (= JCM 13997T = LMG 24279T) Tanasupawat et al. 2007, 1372VP. Microbiology resource announcements 0 40862359
2024 Identification and Characterization of a Novel CCDC6::CASP7 Gene Rearrangement in an Advanced Colorectal Cancer Patient: A Case Report. International journal of molecular sciences 0 39684377

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