{"gene":"CASP7","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1995,"finding":"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.","method":"Bacterially expressed recombinant protein, in vitro protease assay, Sf9 cell apoptosis induction, subunit reconstitution","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of enzymatic activity, subunit mixing, and functional apoptosis assay in one study","pmids":["8521391"],"is_preprint":false},{"year":1996,"finding":"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.","method":"In vitro cleavage assay using bacterially expressed proteins, E. coli expression, DEVD-CHO inhibition","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro cleavage demonstrated with recombinant proteins and defined cleavage sites","pmids":["8755496"],"is_preprint":false},{"year":1996,"finding":"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.","method":"Subcellular fractionation, overexpression in MCF7 cells, western blot detection of processed subunits after Fas/TNF stimulation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization by fractionation, functional overexpression assay, and endogenous processing shown in the same study","pmids":["8576161"],"is_preprint":false},{"year":1996,"finding":"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.","method":"In vitro granzyme B treatment of Jurkat cells with perforin, western blot of endogenous CASP7 processing, apoptosis assay","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — activation of endogenous CASP7 shown in cellulo with functional apoptosis readout, replicated across two papers (PMID 8805307 and 8631895)","pmids":["8805307","8631895"],"is_preprint":false},{"year":1996,"finding":"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.","method":"In vitro cleavage assay with recombinant CMH-1 and granzyme B, N-terminal sequencing to map cleavage sites, activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — precise cleavage site mapped by in vitro reconstitution with site identification, single lab but multiple orthogonal methods","pmids":["8631895"],"is_preprint":false},{"year":1997,"finding":"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.","method":"Temperature-sensitive p53 cell line (LTR6), western blot for caspase processing and substrate cleavage (PARP, lamin B1)","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean genetic epistasis using ts-p53 system, single lab, single method per readout","pmids":["9078237"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis combined with in vitro enzymatic assay and functional cellular/in vivo validation in a single study","pmids":["40533441"],"is_preprint":false}],"current_model":"CASP7 (Mch3/ICE-LAP3/CMH-1) is an executioner cysteine protease that is synthesized as a cytoplasmic zymogen and activated by upstream proteases including CASP3 (which cleaves proCASP7), CASP8/Mch4, and granzyme B (which cleaves at Asp198-Ser199 to generate the active p20/p12 heterodimer); once active it cleaves PARP and lamin B1, and its activity is restrained by XIAP binding to the linker-BIR2 domain, making the XIAP:CASP7 complex a druggable node in apoptosis-resistant cancers."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1995,"claim":"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","pmids":["8521391"],"confidence":"High","gaps":["Did not establish the physiological upstream trigger in human cells","Relative contributions of autoactivation versus CASP3-driven activation not quantified in vivo"]},{"year":1996,"claim":"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","pmids":["8755496"],"confidence":"High","gaps":["In vitro reconstitution only; cellular ordering of CASP8 vs CASP3 input not resolved"]},{"year":1996,"claim":"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","pmids":["8576161"],"confidence":"Medium","gaps":["Single fractionation method for localization","Did not identify which upstream caspase mediates Fas/TNF-induced processing"]},{"year":1996,"claim":"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","pmids":["8631895","8805307"],"confidence":"High","gaps":["Granzyme B cleavage of endogenous CASP7 within intact target cells inferred from processing, not direct enzymology in situ"]},{"year":1997,"claim":"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","pmids":["9078237"],"confidence":"Medium","gaps":["Epistasis between CASP3 and CASP7 not dissected","Single-lab correlative timing rather than loss-of-function proof"]},{"year":2025,"claim":"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","pmids":["40533441"],"confidence":"High","gaps":["Structural detail of the XIAP:CASP7 interface not fully resolved","Selectivity over other caspases of the small molecule not exhaustively defined"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["No proteome-wide substrate map in the timeline","Functional distinction from CASP3 not established by loss-of-function genetics"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,4,5]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,2,5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3]}],"complexes":[],"partners":["CASP3","CASP8","XIAP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P55210","full_name":"Caspase-7","aliases":["Apoptotic protease Mch-3","CMH-1","ICE-like apoptotic protease 3","ICE-LAP3"],"length_aa":303,"mass_kda":34.3,"function":"Thiol protease involved in different programmed cell death processes, such as apoptosis, pyroptosis or granzyme-mediated programmed cell death, by proteolytically cleaving target proteins (PubMed:11257230, PubMed:11257231, PubMed:11701129, PubMed:15314233, PubMed:16916640, PubMed:17646170, PubMed:18723680, PubMed:19581639, PubMed:8521391, PubMed:8567622, PubMed:8576161, PubMed:9070923). Has a marked preference for Asp-Glu-Val-Asp (DEVD) consensus sequences, with some plasticity for alternate non-canonical sequences (PubMed:12824163, PubMed:15314233, PubMed:17697120, PubMed:19581639, PubMed:20566630, PubMed:23650375, PubMed:23897474, PubMed:27032039). Its involvement in the different programmed cell death processes is probably determined by upstream proteases that activate CASP7 (By similarity). Acts as an effector caspase involved in the execution phase of apoptosis: following cleavage and activation by initiator caspases (CASP8, CASP9 and/or CASP10), mediates execution of apoptosis by catalyzing cleavage of proteins, such as CLSPN, PARP1, PTGES3 and YY1 (PubMed:10497198, PubMed:16123041, PubMed:16374543, PubMed:16916640, PubMed:18723680, PubMed:20566630, PubMed:21555521, PubMed:22184066, PubMed:22451931, PubMed:27889207, PubMed:28863261, PubMed:31586028, PubMed:34156061, PubMed:35338844, PubMed:35446120). Compared to CASP3, acts as a minor executioner caspase and cleaves a limited set of target proteins (PubMed:18723680). Acts as a key regulator of the inflammatory response in response to bacterial infection by catalyzing cleavage and activation of the sphingomyelin phosphodiesterase SMPD1 in the extracellular milieu, thereby promoting membrane repair (PubMed:21157428). Regulates pyroptosis in intestinal epithelial cells: cleaved and activated by CASP1 in response to S.typhimurium infection, promoting its secretion to the extracellular milieu, where it catalyzes activation of SMPD1, generating ceramides that repair membranes and counteract the action of gasdermin-D (GSDMD) pores (By similarity). Regulates granzyme-mediated programmed cell death in hepatocytes: cleaved and activated by granzyme B (GZMB) in response to bacterial infection, promoting its secretion to the extracellular milieu, where it catalyzes activation of SMPD1, generating ceramides that repair membranes and counteract the action of perforin (PRF1) pores (By similarity). Following cleavage by CASP1 in response to inflammasome activation, catalyzes processing and inactivation of PARP1, alleviating the transcription repressor activity of PARP1 (PubMed:22464733). Acts as an inhibitor of type I interferon production during virus-induced apoptosis by mediating cleavage of antiviral proteins CGAS, IRF3 and MAVS, thereby preventing cytokine overproduction (By similarity). Cleaves and activates sterol regulatory element binding proteins (SREBPs) (PubMed:8643593). Cleaves phospholipid scramblase proteins XKR4, XKR8 and XKR9 (By similarity). In case of infection, catalyzes cleavage of Kaposi sarcoma-associated herpesvirus protein ORF57, thereby preventing expression of viral lytic genes (PubMed:20159985). Cleaves BIRC6 following inhibition of BIRC6-caspase binding by DIABLO/SMAC (PubMed:36758104, PubMed:36758106) Lacks enzymatic activity","subcellular_location":"Cytoplasm, cytosol; Nucleus; Secreted, extracellular space","url":"https://www.uniprot.org/uniprotkb/P55210/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CASP7","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000165806","cell_line_id":"CID001708","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3},{"compartment":"big_aggregates","grade":2}],"interactors":[],"url":"https://opencell.sf.czbiohub.org/target/CID001708","total_profiled":1310},"omim":[{"mim_id":"617647","title":"PROSTATE CANCER-ASSOCIATED TRANSCRIPT 18, NONCODING; PCAT18","url":"https://www.omim.org/entry/617647"},{"mim_id":"616466","title":"UNC5 NETRIN RECEPTOR D; UNC5D","url":"https://www.omim.org/entry/616466"},{"mim_id":"612787","title":"PSEUDOURIDYLATE SYNTHASE 10; PUS10","url":"https://www.omim.org/entry/612787"},{"mim_id":"612770","title":"PHOSPHATIDYLSERINE DECARBOXYLASE; PISD","url":"https://www.omim.org/entry/612770"},{"mim_id":"612218","title":"ZINC FINGER- AND BTB DOMAIN-CONTAINING PROTEIN 38; ZBTB38","url":"https://www.omim.org/entry/612218"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli fibrillar center","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CASP7"},"hgnc":{"alias_symbol":["MCH3","CMH-1","ICE-LAP3"],"prev_symbol":[]},"alphafold":{"accession":"P55210","domains":[{"cath_id":"3.40.50.1460","chopping":"59-191_214-295","consensus_level":"high","plddt":94.9727,"start":59,"end":295}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P55210","model_url":"https://alphafold.ebi.ac.uk/files/AF-P55210-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P55210-F1-predicted_aligned_error_v6.png","plddt_mean":81.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CASP7","jax_strain_url":"https://www.jax.org/strain/search?query=CASP7"},"sequence":{"accession":"P55210","fasta_url":"https://rest.uniprot.org/uniprotkb/P55210.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P55210/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P55210"}},"corpus_meta":[{"pmid":"8755496","id":"PMC_8755496","title":"In vitro 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panicea</i>","date":"2024-11-13","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.11.623018","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23824,"output_tokens":2026,"usd":0.050931,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8810,"output_tokens":2449,"usd":0.052637,"stage2_stop_reason":"end_turn"},"total_usd":0.103568,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"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.\",\n      \"method\": \"Bacterially expressed recombinant protein, in vitro protease assay, Sf9 cell apoptosis induction, subunit reconstitution\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of enzymatic activity, subunit mixing, and functional apoptosis assay in one study\",\n      \"pmids\": [\"8521391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro cleavage assay using bacterially expressed proteins, E. coli expression, DEVD-CHO inhibition\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro cleavage demonstrated with recombinant proteins and defined cleavage sites\",\n      \"pmids\": [\"8755496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"Subcellular fractionation, overexpression in MCF7 cells, western blot detection of processed subunits after Fas/TNF stimulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization by fractionation, functional overexpression assay, and endogenous processing shown in the same study\",\n      \"pmids\": [\"8576161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro granzyme B treatment of Jurkat cells with perforin, western blot of endogenous CASP7 processing, apoptosis assay\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — activation of endogenous CASP7 shown in cellulo with functional apoptosis readout, replicated across two papers (PMID 8805307 and 8631895)\",\n      \"pmids\": [\"8805307\", \"8631895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro cleavage assay with recombinant CMH-1 and granzyme B, N-terminal sequencing to map cleavage sites, activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — precise cleavage site mapped by in vitro reconstitution with site identification, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"8631895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"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.\",\n      \"method\": \"Temperature-sensitive p53 cell line (LTR6), western blot for caspase processing and substrate cleavage (PARP, lamin B1)\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean genetic epistasis using ts-p53 system, single lab, single method per readout\",\n      \"pmids\": [\"9078237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis combined with in vitro enzymatic assay and functional cellular/in vivo validation in a single study\",\n      \"pmids\": [\"40533441\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CASP7 (Mch3/ICE-LAP3/CMH-1) is an executioner cysteine protease that is synthesized as a cytoplasmic zymogen and activated by upstream proteases including CASP3 (which cleaves proCASP7), CASP8/Mch4, and granzyme B (which cleaves at Asp198-Ser199 to generate the active p20/p12 heterodimer); once active it cleaves PARP and lamin B1, and its activity is restrained by XIAP binding to the linker-BIR2 domain, making the XIAP:CASP7 complex a druggable node in apoptosis-resistant cancers.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #5]. 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 [#0, #2, #4]. 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 [#0, #1, #3, #4]. 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 [#2, #5]. 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 [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"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.\",\n      \"evidence\": \"Bacterially expressed recombinant Mch3, in vitro PARP cleavage assay, subunit reconstitution with CPP32, and Sf9 apoptosis induction\",\n      \"pmids\": [\"8521391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the physiological upstream trigger in human cells\", \"Relative contributions of autoactivation versus CASP3-driven activation not quantified in vivo\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro cleavage assays with bacterially expressed proMch3, CASP8 and granzyme B; DEVD-CHO inhibition\",\n      \"pmids\": [\"8755496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro reconstitution only; cellular ordering of CASP8 vs CASP3 input not resolved\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"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.\",\n      \"evidence\": \"Subcellular fractionation, overexpression in MCF7 cells, western blot of processed subunits after Fas/TNF stimulation\",\n      \"pmids\": [\"8576161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single fractionation method for localization\", \"Did not identify which upstream caspase mediates Fas/TNF-induced processing\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro cleavage with recombinant CMH-1 and granzyme B, N-terminal sequencing, activity assays, and granzyme B/perforin treatment of Jurkat cells\",\n      \"pmids\": [\"8631895\", \"8805307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Granzyme B cleavage of endogenous CASP7 within intact target cells inferred from processing, not direct enzymology in situ\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Integrated CASP7 into the p53-dependent intrinsic apoptotic pathway, showing it is activated alongside CASP3 with coincident PARP and lamin B1 cleavage.\",\n      \"evidence\": \"Temperature-sensitive p53 LTR6 cell line, western blot for caspase processing and substrate cleavage\",\n      \"pmids\": [\"9078237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Epistasis between CASP3 and CASP7 not dissected\", \"Single-lab correlative timing rather than loss-of-function proof\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Virtual screening, in vitro binding, D93 site-directed mutagenesis, caspase activity and viability assays in CASP3/DR lines, and in vivo xenograft\",\n      \"pmids\": [\"40533441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the XIAP:CASP7 interface not fully resolved\", \"Selectivity over other caspases of the small molecule not exhaustively defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No proteome-wide substrate map in the timeline\", \"Functional distinction from CASP3 not established by loss-of-function genetics\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 4, 5]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CASP3\", \"CASP8\", \"XIAP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}