Calpain-3 (CAPN3/p94) is an intracellular calcium-dependent cysteine endopeptidase enriched in skeletal muscle. It binds titin and undergoes rapid, regulated autolysis, coupling proteolytic activity and changing sarcomeric localization to muscle maintenance and adaptation. Mouse genetic and biochemical studies also support a nonproteolytic contribution to the organization of sarcoplasmic-reticulum-associated proteins and calcium release. Other experimental contexts implicate CAPN3 in myoblast reserve-cell formation, selective signaling-protein turnover, and Def/UTP25-associated nucleolar p53 turnover. These activities depend on cell context and the CAPN3 construct or isoform examined. Pathogenic human CAPN3 variants cause calpainopathy, including recessive and dominant limb-girdle muscular dystrophy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003824 catalytic activity | IDA PMID:9642272 Functional defects of a muscle-specific calpain, p94, caused... | MODIFY | Summary: CAPN3 catalyzes calcium-dependent cysteine endoproteolysis. Reason: The disease-mutant assays in PMID:9642272 establish proteolytic activity rather than an unspecified catalytic reaction. Calcium-dependent autolysis and native human-muscle measurements reinforce the specific calpain activity. Replace the uninformative catalytic ancestor with GO:0004198; this does not assign a unique physiological substrate. Proposed replacements: calcium-dependent cysteine-type endopeptidase activity |
| GO:0004198 calcium-dependent cysteine-type endopeptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Calcium-dependent cysteine endopeptidase activity is the central conserved enzymatic function. Reason: This PAINT inference is consistent with the CAPN3 catalytic machinery, direct human CAPN3 mutant assays, and calcium-dependent activity. The listed PTN is preserved as the asserted ancestral node; no uninspected IBD placement or donor count is used to invent an evolutionary defect. |
| GO:0004198 calcium-dependent cysteine-type endopeptidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: CAPN3 is a calcium-dependent cysteine endopeptidase. Reason: The domain/EC and ortholog transfers agree with experimental CAPN3 activity: disease variants compromise fodrin proteolysis, the isolated protease core undergoes calcium-dependent autolysis, and endogenous human CAPN3 responds to calcium. The original evidence codes and mouse/rat source identities are retained; activity is not inferred for every truncated alternative product. |
| GO:0004198 calcium-dependent cysteine-type endopeptidase activity | ISS GO_REF:0000024 | ACCEPT | Summary: CAPN3 is a calcium-dependent cysteine endopeptidase. Reason: The domain/EC and ortholog transfers agree with experimental CAPN3 activity: disease variants compromise fodrin proteolysis, the isolated protease core undergoes calcium-dependent autolysis, and endogenous human CAPN3 responds to calcium. The original evidence codes and mouse/rat source identities are retained; activity is not inferred for every truncated alternative product. |
| GO:0004198 calcium-dependent cysteine-type endopeptidase activity | ISS GO_REF:0000024 | ACCEPT | Summary: CAPN3 is a calcium-dependent cysteine endopeptidase. Reason: The domain/EC and ortholog transfers agree with experimental CAPN3 activity: disease variants compromise fodrin proteolysis, the isolated protease core undergoes calcium-dependent autolysis, and endogenous human CAPN3 responds to calcium. The original evidence codes and mouse/rat source identities are retained; activity is not inferred for every truncated alternative product. |
| GO:0004198 calcium-dependent cysteine-type endopeptidase activity | TAS PMID:9642272 Functional defects of a muscle-specific calpain, p94, caused... | ACCEPT | Summary: CAPN3 is a calcium-dependent cysteine endopeptidase. Reason: The domain/EC and ortholog transfers agree with experimental CAPN3 activity: disease variants compromise fodrin proteolysis, the isolated protease core undergoes calcium-dependent autolysis, and endogenous human CAPN3 responds to calcium. The original evidence codes and mouse/rat source identities are retained; activity is not inferred for every truncated alternative product. |
| GO:0005509 calcium ion binding | IEA GO_REF:0000120 | ACCEPT | Summary: Calcium binding supports CAPN3 protease regulation. Reason: The reviewed human UniProt record contains experimentally grounded calcium-binding features in the calpain architecture, and calcium-dependent autolysis is supported by recombinant-core and native-muscle studies. This supports the existing mouse/domain transfers without extending calcium dependence to a proven physiological sodium-sensor mechanism. |
| GO:0005509 calcium ion binding | ISS GO_REF:0000024 | ACCEPT | Summary: Calcium binding supports CAPN3 protease regulation. Reason: The reviewed human UniProt record contains experimentally grounded calcium-binding features in the calpain architecture, and calcium-dependent autolysis is supported by recombinant-core and native-muscle studies. This supports the existing mouse/domain transfers without extending calcium dependence to a proven physiological sodium-sensor mechanism. |
| GO:0005515 protein binding | IPI PMID:20860623 A new pathway encompassing calpain 3 and its newly identifie... | MODIFY | Summary: The recorded interaction partner is titin. Reason: The source interaction names Q8WZ42, and the CARP study places CAPN3 in the titin-associated sarcomeric pathway. Direct titin interaction and its suppression of CAPN3 autolysis are independently supported by PMID:18310072. Titin binding is more informative than generic protein binding; the CARP cleavage finding is not conflated with titin being the cleaved substrate. Proposed replacements: titin binding |
| GO:0005515 protein binding | IPI PMID:23357851 Def defines a conserved nucleolar pathway that leads p53 to ... | KEEP AS NON CORE | Summary: CAPN3 associates with Def/UTP25 in a context-dependent nucleolar turnover pathway. Reason: The full paper includes human CAPN3 knockdown and human Def-CAPN3 co-immunoprecipitation in human cells, in addition to zebrafish experiments. Thus the interaction is not rejected as a zebrafish-only observation. Def is the recruiting factor; the CAPN3 association does not establish an adaptor activity for CAPN3 itself. Retain the supported interaction as non-core. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:23414517 A human skeletal muscle interactome centered on proteins inv... | MODIFY | Summary: The muscle-interactome interaction is specifically with titin. Reason: Q8WZ42 is the recorded partner in this human muscle interaction resource. The specific titin association agrees with independent focused CAPN3-titin experiments, so GO:0031432 captures the interaction more usefully. A network edge alone is not used to infer cleavage, complex stoichiometry, or a novel adaptor mechanism. Proposed replacements: titin binding |
| GO:0005515 protein binding | IPI PMID:23707407 PLEIAD/SIMC1/C5orf25, a novel autolysis regulator for a skel... | KEEP AS NON CORE | Summary: CAPN3 binds its autolysis regulator PLEIAD/SIMC1. Reason: The primary Results show CAPN3-PLEIAD association and suppression of autolysis/fodrin cleavage. PLEIAD recruits CTBP1 and is the proposed scaffold; CAPN3 is the protease. The authenticated normal-fetch full-text variant was read separately from the preserved abstract-only canonical cache. No more specific CAPN3 binding function is established by these experiments. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: A binary interaction with NTAQ1 is supported by the human interaction screen. Reason: The primary Interactome Atlas CAPN3 table lists the HI-II-14 edge to WDYHV1; the official human NCBI Gene record identifies WDYHV1 as NTAQ1 and links Q96HA8. This corroborates the exact source partner. A yeast-two-hybrid interaction does not establish that NTAQ1 is a CAPN3 substrate or that CAPN3 executes an N-degron pathway step. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: The screen supports CAPN3 association with OSGIN1. Reason: The primary Interactome Atlas CAPN3 table explicitly lists OSGIN1 under HI-II-14, corroborating the recorded Q9UJX0 interaction. The edge is retained as a non-core association; a substrate, regulatory outcome, or stable native complex is not inferred from the screen. Supporting Evidence: |
| GO:0005515 protein binding | IPI P20807-2 PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | KEEP AS NON CORE | Summary: The recorded P20807-2 product has an interaction with TFCP2. Reason: The primary Interactome Atlas lists the CAPN3-TFCP2 Yang-16 edge, consistent with the isoform-interaction study. The source P20807-2 field is preserved exactly. The gene-level portal corroborates the edge but does not independently resolve the tested isoform construct; no binding is generalized to all five products or converted into a transcription-factor function for CAPN3. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:27657329 Phosphorylation of Def Regulates Nucleolar p53 Turnover and ... | KEEP AS NON CORE | Summary: Human CAPN3 associates directly with Def/UTP25 under the reported construct conditions. Reason: Human-cell co-immunoprecipitation and a recombinant GST-CAPN3/His-Def fragment pull-down support association. The Methods state that the human CAPN3 expression constructs exclude IS1; that construct is not silently equated with the canonical full-length product or with P20807-2. Def-mediated recruitment does not make CAPN3 the molecular adaptor. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | KEEP AS NON CORE | Summary: The CAPN3-OSGIN1 interaction is supported, while variant-specific effects remain unassessed here. Reason: The original source records Q9UJX0 in the human variation interaction study. Independent primary HI-II-14 evidence supports the same gene-pair interaction, so the generic association can be retained without asserting a particular allele effect. The 2019 target-specific variant table has not been inspected; no variant-dependent mechanism or substrate identity is inferred. |
| GO:0005634 nucleus | IDA PMID:19386580 Novel variants of muscle calpain 3 identified in human melan... | KEEP AS NON CORE | Summary: Nuclear localization occurs in the melanoma-variant context. Reason: The human melanoma study reports noncanonical CAPN3 variants and nuclear/nucleolar localization. The curated IDA location is retained as context dependent, without assigning the hMp78/hMp84 species to one of the five machine-listed products or claiming that the major muscle pool is constitutively nuclear. Full text of this original study remains unavailable. Supporting Evidence: |
| GO:0005730 nucleolus | IDA PMID:27657329 Phosphorylation of Def Regulates Nucleolar p53 Turnover and ... | KEEP AS NON CORE | Summary: A nucleolar CAPN3 pool is supported in human cultured cells. Reason: The human-cell experiments in PMID:27657329 detect endogenous nucleolar CAPN3 species and show Def-dependent recruitment. Recombinant human constructs exclude IS1, whereas the endogenous observations provide a separate localization line of evidence. Retain this specialized compartment without making it the predominant location of skeletal-muscle CAPN3. |
| GO:0005730 nucleolus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: A nucleolar CAPN3 pool is supported in human cultured cells. Reason: The human-cell experiments in PMID:27657329 detect endogenous nucleolar CAPN3 species and show Def-dependent recruitment. Recombinant human constructs exclude IS1, whereas the endogenous observations provide a separate localization line of evidence. Retain this specialized compartment without making it the predominant location of skeletal-muscle CAPN3. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: CAPN3 has a conserved cytoplasmic distribution. Reason: The PAINT assertion agrees with human muscle and cellular observations and with CAPN3 cytosolic/sarcomeric functions. P20807 occurring among descendants is legitimate target experimental grounding, not circular propagation. The source PTN is preserved without claiming to have reconstructed its IBD placement. |
| GO:0005737 cytoplasm | IDA PMID:19386580 Novel variants of muscle calpain 3 identified in human melan... | ACCEPT | Summary: The human melanoma CAPN3 variants are detected in the cytoplasm. Reason: The source abstract explicitly reports predominantly cytoplasmic and nucleolar distribution. This supports the broad cytoplasmic location but does not identify these cancer-cell variants with a specific machine-listed product. The same broad compartment is compatible with the established muscle function. Supporting Evidence: |
| GO:0005737 cytoplasm | IDA PMID:19556129 Immunohistochemical analysis of calpain 3: advantages and li... | ACCEPT | Summary: CAPN3 is detected in human muscle cytoplasm. Reason: The human muscle immunohistochemistry study supports the curated broad location while emphasizing antibody-dependent diagnostic limitations. Retain the IDA compartment in agreement with independent native-muscle fractionation; no finer membrane topology or sub-sarcomeric location is inferred from the abstract alone. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Cytoplasmic/cytosolic CAPN3 pools are biologically well supported. Reason: The mouse/controlled-vocabulary inferences agree with human cellular and muscle observations. Native human-muscle fractionation shows redistribution of sufficiently autolysed CAPN3 to a cytosolic fraction; this is compatible with a large bound sarcomeric pool and does not imply that all CAPN3 is freely soluble at rest. |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: Cytoplasmic/cytosolic CAPN3 pools are biologically well supported. Reason: The mouse/controlled-vocabulary inferences agree with human cellular and muscle observations. Native human-muscle fractionation shows redistribution of sufficiently autolysed CAPN3 to a cytosolic fraction; this is compatible with a large bound sarcomeric pool and does not imply that all CAPN3 is freely soluble at rest. |
| GO:0005829 cytosol | ISS GO_REF:0000024 | ACCEPT | Summary: Cytoplasmic/cytosolic CAPN3 pools are biologically well supported. Reason: The mouse/controlled-vocabulary inferences agree with human cellular and muscle observations. Native human-muscle fractionation shows redistribution of sufficiently autolysed CAPN3 to a cytosolic fraction; this is compatible with a large bound sarcomeric pool and does not imply that all CAPN3 is freely soluble at rest. |
| GO:0005886 plasma membrane | IEA GO_REF:0000107 | UNDECIDED | Summary: The exact plasma-membrane assignment needs localization evidence beyond triad association. Reason: CAPN3 associates with muscle membrane/triad fractions, but the later primary work distinguishes SR-associated complexes from T-tubule markers. Neither mixed microsomal fractionation nor the existence of the source rodent transfer independently establishes the plasma-membrane subcompartment for human CAPN3. Preserve the assertions pending the exact donor localization experiment; absence of a transmembrane segment is not used as a refutation. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | UNDECIDED | Summary: The exact plasma-membrane assignment needs localization evidence beyond triad association. Reason: CAPN3 associates with muscle membrane/triad fractions, but the later primary work distinguishes SR-associated complexes from T-tubule markers. Neither mixed microsomal fractionation nor the existence of the source rodent transfer independently establishes the plasma-membrane subcompartment for human CAPN3. Preserve the assertions pending the exact donor localization experiment; absence of a transmembrane segment is not used as a refutation. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | UNDECIDED | Summary: The exact plasma-membrane assignment needs localization evidence beyond triad association. Reason: CAPN3 associates with muscle membrane/triad fractions, but the later primary work distinguishes SR-associated complexes from T-tubule markers. Neither mixed microsomal fractionation nor the existence of the source rodent transfer independently establishes the plasma-membrane subcompartment for human CAPN3. Preserve the assertions pending the exact donor localization experiment; absence of a transmembrane segment is not used as a refutation. |
| GO:0006508 proteolysis | IBA GO_REF:0000033 | ACCEPT | Summary: Proteolysis is a conserved CAPN3 function. Reason: The PAINT inference is independently grounded by human CAPN3 enzymatic experiments. The target in the descendant list is legitimate support for the ancestral inference, not circularity. This broad process does not require every proposed physiological substrate to be confirmed. |
| GO:0006508 proteolysis | IDA PMID:18310072 Multiple molecular interactions implicate the connectin/titi... | ACCEPT | Summary: CAPN3 proteolyzes associated regulatory proteins in the titin pathway. Reason: The source reports CAPN3 cleavage of MARP2 alongside titin-mediated suppression of autolysis. Retain the experimentally supported proteolysis process, distinguishing the protease from the titin scaffold and avoiding the inference that every interacting protein is a native substrate. Supporting Evidence: |
| GO:0006508 proteolysis | IDA PMID:19386580 Novel variants of muscle calpain 3 identified in human melan... | ACCEPT | Summary: The curated proteolysis activity agrees with the established CAPN3 enzyme function. Reason: The melanoma paper concerns unusual human CAPN3 variants and their instability. Its abstract does not independently expose every IDA assay, so the original experiment is not overinterpreted. Nonetheless proteolysis is directly established for CAPN3 in other primary studies, and there is no basis to reject the curator-supported general process. |
| GO:0006508 proteolysis | IDA PMID:20694146 Calpain 3 is a rapid-action, unidirectional proteolytic swit... | ACCEPT | Summary: CAPN3 directly proteolyzes selected signaling proteins in human-cell assays. Reason: The primary study validates cleavage of selected PIAS proteins and other candidates in active-versus-inactive CAPN3 experiments. Its large predicted-substrate list is not treated as direct validation of each member. The selective cleavages support the broad proteolysis process. Supporting Evidence: |
| GO:0006508 proteolysis | IDA PMID:9642272 Functional defects of a muscle-specific calpain, p94, caused... | ACCEPT | Summary: Proteolysis is the direct catalytic process executed by CAPN3. Reason: The original disease-variant work and independent human-cell studies establish proteolytic activity. The electronic domain mapping is consistent with that evidence. Disease necessity alone is not the basis for this assignment: CAPN3 itself supplies the protease activity. |
| GO:0006508 proteolysis | IEA GO_REF:0000120 | ACCEPT | Summary: Proteolysis is the direct catalytic process executed by CAPN3. Reason: The original disease-variant work and independent human-cell studies establish proteolytic activity. The electronic domain mapping is consistent with that evidence. Disease necessity alone is not the basis for this assignment: CAPN3 itself supplies the protease activity. |
| GO:0006915 apoptotic process | TAS PMID:19386580 Novel variants of muscle calpain 3 identified in human melan... | UNDECIDED | Summary: The melanoma-variant association does not yet establish CAPN3 execution of an apoptotic step. Reason: The accessible source abstract describes cisplatin-associated changes in unusual CAPN3 variants and apoptosis-associated changes, with calpeptin treatment. Drug correlation and a nonselective calpain inhibitor do not isolate CAPN3 participation. The full experimental source could not be inspected, so the TAS assertion is retained undecided rather than declared false or generalized to muscle CAPN3. Supporting Evidence: |
| GO:0007517 muscle organ development | TAS PMID:7720071 Mutations in the proteolytic enzyme calpain 3 cause limb-gir... | UNDECIDED | Summary: Muscle disease and enzyme defects do not by themselves identify an organ-development step. Reason: The respective original sources establish human calpainopathy or mutant enzyme defects. Their accessible abstracts do not establish CAPN3 participation in formation of the muscle organ. Maintenance and adaptation are well supported elsewhere, but that does not settle this developmental TAS claim; the original source assertion is preserved pending direct developmental evidence. |
| GO:0007517 muscle organ development | TAS PMID:9642272 Functional defects of a muscle-specific calpain, p94, caused... | UNDECIDED | Summary: Muscle disease and enzyme defects do not by themselves identify an organ-development step. Reason: The respective original sources establish human calpainopathy or mutant enzyme defects. Their accessible abstracts do not establish CAPN3 participation in formation of the muscle organ. Maintenance and adaptation are well supported elsewhere, but that does not settle this developmental TAS claim; the original source assertion is preserved pending direct developmental evidence. |
| GO:0008233 peptidase activity | IDA PMID:23707407 PLEIAD/SIMC1/C5orf25, a novel autolysis regulator for a skel... | MODIFY | Summary: The assayed peptidase is the calcium-dependent cysteine endopeptidase CAPN3. Reason: The PLEIAD study tests CAPN3 autolysis, fodrin cleavage and cleavage of CTBP1 in cell-expression assays. Mouse primary-cell endogenous CTBP1 cleavage remained below detection, so native-substrate certainty is not claimed. The specific enzyme class is nevertheless established and is more informative than generic peptidase activity. Proposed replacements: calcium-dependent cysteine-type endopeptidase activity |
| GO:0008233 peptidase activity | IDA PMID:9642272 Functional defects of a muscle-specific calpain, p94, caused... | MODIFY | Summary: The source enzyme assays establish a specific calpain activity. Reason: PMID:9642272 assays loss of CAPN3 proteolytic function in disease-associated mutants. Together with calcium-dependent activity, this supports replacement of peptidase activity by GO:0004198 rather than a nonspecific catalytic ancestor. Proposed replacements: calcium-dependent cysteine-type endopeptidase activity |
| GO:0008234 cysteine-type peptidase activity | IDA PMID:20694146 Calpain 3 is a rapid-action, unidirectional proteolytic swit... | MODIFY | Summary: CAPN3 has calcium-dependent cysteine endopeptidase activity. Reason: The biochemical work, original molecular identification, and enzyme architecture support the specific calcium-dependent endopeptidase class. The broader cysteine peptidase assertion is not false, but GO:0004198 more accurately describes the reviewed activity. This refinement does not imply identical activity of every alternative product. Proposed replacements: calcium-dependent cysteine-type endopeptidase activity |
| GO:0008234 cysteine-type peptidase activity | IEA GO_REF:0000117 | MODIFY | Summary: CAPN3 has calcium-dependent cysteine endopeptidase activity. Reason: The biochemical work, original molecular identification, and enzyme architecture support the specific calcium-dependent endopeptidase class. The broader cysteine peptidase assertion is not false, but GO:0004198 more accurately describes the reviewed activity. This refinement does not imply identical activity of every alternative product. Proposed replacements: calcium-dependent cysteine-type endopeptidase activity |
| GO:0008234 cysteine-type peptidase activity | TAS PMID:2555341 Molecular cloning of a novel mammalian calcium-dependent pro... | MODIFY | Summary: CAPN3 has calcium-dependent cysteine endopeptidase activity. Reason: The biochemical work, original molecular identification, and enzyme architecture support the specific calcium-dependent endopeptidase class. The broader cysteine peptidase assertion is not false, but GO:0004198 more accurately describes the reviewed activity. This refinement does not imply identical activity of every alternative product. Proposed replacements: calcium-dependent cysteine-type endopeptidase activity |
| GO:0008307 structural constituent of muscle | IEA GO_REF:0000107 | ACCEPT | Summary: CAPN3 makes a nonproteolytic contribution to muscle structural integrity. Reason: GO:0008307 requires a contribution to muscle-fiber integrity, not exclusive load bearing or a completely resolved tether. PMID:21295580 explicitly contrasts sarcomere/thick-filament disorganization in null mice with preserved alignment in catalytically inactive C129S mice, and reports preserved triad morphology and calcium-release function with C129S. Together with CAPN3 binding and selective recruitment of aldolase A in PMID:18676612, this supports a physical organizing contribution rather than inferring structure only from dystrophy. Retain the existing ortholog-supported structural assignment. Its broad outcome overlaps the more informative adaptor mechanism summarized in the core; neither a direct CAPN3-RyR interface, a specific titin-to-triad bridge nor the withdrawn hexamer model is established. |
| GO:0008307 structural constituent of muscle | ISS GO_REF:0000024 | ACCEPT | Summary: CAPN3 makes a nonproteolytic contribution to muscle structural integrity. Reason: GO:0008307 requires a contribution to muscle-fiber integrity, not exclusive load bearing or a completely resolved tether. PMID:21295580 explicitly contrasts sarcomere/thick-filament disorganization in null mice with preserved alignment in catalytically inactive C129S mice, and reports preserved triad morphology and calcium-release function with C129S. Together with CAPN3 binding and selective recruitment of aldolase A in PMID:18676612, this supports a physical organizing contribution rather than inferring structure only from dystrophy. Retain the existing ortholog-supported structural assignment. Its broad outcome overlaps the more informative adaptor mechanism summarized in the core; neither a direct CAPN3-RyR interface, a specific titin-to-triad bridge nor the withdrawn hexamer model is established. |
| GO:0012501 programmed cell death | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Candidate-substrate proteomics does not demonstrate CAPN3 participation in a programmed-cell-death pathway. Reason: The inspected MGI donor record associates this mouse process with PMID:20460380. Its controlled WT-versus-C129S extract proteomics identifies candidate substrates under sodium or calcium incubation, rather than a CAPN3-dependent sequence of events ending in cell death as required by GO:0012501. A candidate protein having a death-related function does not establish that cleavage executes or regulates death in a cell. The human melanoma abstract in PMID:19386580 concerns distinct variants, cisplatin-associated changes and calpeptin; it cannot supply the missing mechanistic link for this mouse-derived electronic assertion. Mark the transferred process as over-annotated while leaving the separate original melanoma apoptotic-process row undecided because its full evidence remains unavailable. |
| GO:0014718 positive regulation of satellite cell activation involved in skeletal muscle regeneration | IEA GO_REF:0000107 | MODIFY | Summary: The recovered mouse evidence supports regulation of myoblast differentiation and reserve-cell formation. Reason: The donor study promotes formation of quiescent reserve cells through reduced MyoD abundance; it does not directly demonstrate activation of quiescent satellite cells into G1/division, which is required by GO:0014718. Its loss- and gain-of-function experiments support the broader regulation-of-myoblast-differentiation process. Retain the mouse-to-human inference at that scope, without identifying C2C12 reserve cells as directly assayed adult human satellite cells. Proposed replacements: regulation of myoblast differentiation Supporting Evidence: |
| GO:0014718 positive regulation of satellite cell activation involved in skeletal muscle regeneration | ISS GO_REF:0000024 | MODIFY | Summary: The recovered mouse evidence supports regulation of myoblast differentiation and reserve-cell formation. Reason: The donor study promotes formation of quiescent reserve cells through reduced MyoD abundance; it does not directly demonstrate activation of quiescent satellite cells into G1/division, which is required by GO:0014718. Its loss- and gain-of-function experiments support the broader regulation-of-myoblast-differentiation process. Retain the mouse-to-human inference at that scope, without identifying C2C12 reserve cells as directly assayed adult human satellite cells. Proposed replacements: regulation of myoblast differentiation Supporting Evidence: |
| GO:0014850 response to muscle activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: CAPN3 participates in adaptation to muscle activity. Reason: The rat transfer is consistent with the mouse C129S knock-in exercise study, which connects protease-dependent redistribution to adaptation to physical stress. This is a physiological context for the muscle function, not a distinct catalytic activity. The exact rat experiment has not been reconstructed, and immediate activation by every contraction is not implied. |
| GO:0030016 myofibril | ISS GO_REF:0000024 | ACCEPT | Summary: Myofibrillar association is a major CAPN3 location. Reason: Titin binding, sarcomeric redistribution and native-muscle fractionation independently support a myofibrillar CAPN3 pool. The rat source transfer agrees with these data. This broad location does not resolve every M-line, N2A or Z-disc population. |
| GO:0030018 Z disc | ISS GO_REF:0000024 | UNDECIDED | Summary: The precise Z-disc localization requires its donor experiment. Reason: CAPN3-titin binding and localization near sarcomeric landmarks do not alone distinguish the Z disc from the N2A region, M line or adjacent triad. The rat-specific source experiment has not been recovered in sufficient detail to adjudicate this fine compartment. Preserve the assertion without treating neighboring localization as either proof or contradiction. |
| GO:0030163 protein catabolic process | IDA PMID:27657329 Phosphorylation of Def Regulates Nucleolar p53 Turnover and ... | KEEP AS NON CORE | Summary: CAPN3 contributes to p53 turnover in the reported nucleolar pathway. Reason: The study includes endogenous human-cell localization/recruitment and recombinant or cell-extract cleavage experiments. Human CAPN3 constructs lack IS1, and purified CAPN3 was incubated with p53-containing extracts rather than a completely purified two-protein system. These limits do not negate the demonstrated context-dependent protein catabolism, but it is not treated as the principal muscle function. Supporting Evidence: |
| GO:0030163 protein catabolic process | IMP PMID:23357851 Def defines a conserved nucleolar pathway that leads p53 to ... | KEEP AS NON CORE | Summary: Human CAPN3 depletion stabilizes p53 in the Def pathway. Reason: The full paper tests human CAPN3-specific knockdown and p53 abundance in human cells as well as zebrafish. The perturbation supports CAPN3-dependent catabolism in this context; it does not by itself prove a purified binary cleavage reaction or establish that all CAPN3 isoforms execute it. Supporting Evidence: |
| GO:0030239 myofibril assembly | ISS GO_REF:0000024 | UNDECIDED | Summary: Myofibril formation is not resolved by the evidence for maintenance and remodeling. Reason: CAPN3 deficiency and protease inactivation affect muscle integrity, and titin-associated dynamics are experimentally supported. However, the exact mouse assembly experiment and the full original 1998 basis for this TAS assignment were not inspected. Formation of a myofibril should not be inferred solely from damage to an existing one; preserve both source assertions pending that distinction. |
| GO:0030239 myofibril assembly | TAS PMID:9642272 Functional defects of a muscle-specific calpain, p94, caused... | UNDECIDED | Summary: Myofibril formation is not resolved by the evidence for maintenance and remodeling. Reason: CAPN3 deficiency and protease inactivation affect muscle integrity, and titin-associated dynamics are experimentally supported. However, the exact mouse assembly experiment and the full original 1998 basis for this TAS assignment were not inspected. Formation of a myofibril should not be inferred solely from damage to an existing one; preserve both source assertions pending that distinction. |
| GO:0030315 T-tubule | ISS GO_REF:0000024 | UNDECIDED | Summary: The T-tubule subcompartment is not settled by mixed triad localization. Reason: The source is a rat transfer whose precise localization experiment has not been recovered. Later mouse work specifically finds SR-component co-association rather than DHPR co-immunoprecipitation, but that does not exclude a separate rat T-tubule pool. Keep the source undecided instead of moving an experimental assertion solely on the basis of another species or assay. Supporting Evidence: |
| GO:0031402 sodium ion binding | IEA GO_REF:0000107 | UNDECIDED | Summary: Sodium binding and physiological sodium-dependent activation require separate adjudication. Reason: The original study infers a shared calcium/sodium-sensitive site from mutagenesis and assays extracts plus treated living myotubes. The later native-muscle study finds sodium-associated autolysis only when physiological potassium is absent and explicitly still considers nonphysiological sodium binding plausible. GO:0031402 describes binding itself, so loss of physiological activation does not disprove binding; conversely ion-dependent autolysis is not a direct binding measurement. Preserve this unresolved mechanistic transfer. Supporting Evidence: PMID:37298357 but this only occurred if all K+ normally present in a muscle cell was absent |
| GO:0031402 sodium ion binding | ISS GO_REF:0000024 | UNDECIDED | Summary: Sodium binding and physiological sodium-dependent activation require separate adjudication. Reason: The original study infers a shared calcium/sodium-sensitive site from mutagenesis and assays extracts plus treated living myotubes. The later native-muscle study finds sodium-associated autolysis only when physiological potassium is absent and explicitly still considers nonphysiological sodium binding plausible. GO:0031402 describes binding itself, so loss of physiological activation does not disprove binding; conversely ion-dependent autolysis is not a direct binding measurement. Preserve this unresolved mechanistic transfer. |
| GO:0031432 titin binding | IPI PMID:18310072 Multiple molecular interactions implicate the connectin/titi... | ACCEPT | Summary: Direct titin binding anchors CAPN3 in its muscle context. Reason: The focused titin study and disease-variant experiments establish binding to titin regions and distinguish this interaction from proteolytic activity: some inactive disease mutants retain titin binding. Titin also suppresses CAPN3 autolysis. The withdrawn hexamer study is not used to support this independently established interaction. |
| GO:0031432 titin binding | IPI PMID:9642272 Functional defects of a muscle-specific calpain, p94, caused... | ACCEPT | Summary: Direct titin binding anchors CAPN3 in its muscle context. Reason: The focused titin study and disease-variant experiments establish binding to titin regions and distinguish this interaction from proteolytic activity: some inactive disease mutants retain titin binding. Titin also suppresses CAPN3 autolysis. The withdrawn hexamer study is not used to support this independently established interaction. |
| GO:0031648 protein destabilization | IMP PMID:23357851 Def defines a conserved nucleolar pathway that leads p53 to ... | KEEP AS NON CORE | Summary: CAPN3 contributes to destabilization of p53 in human cells. Reason: Human CAPN3-specific perturbation in the Def study alters p53 abundance and the downstream p53 pathway. This supports context-dependent destabilization without claiming that CAPN3 is a general proteostasis regulator or silently substituting zebrafish Capn3b for the human experiments. Supporting Evidence: |
| GO:0032991 protein-containing complex | IEA GO_REF:0000107 | ACCEPT | Summary: CAPN3 associates with muscle protein complexes. Reason: Focused mouse triad and SR experiments support co-complex association of CAPN3 with muscle components. The broad protein-containing-complex term is reasonable without assigning a named stoichiometric assembly or requiring direct binding to every co-immunoprecipitated partner. This does not invoke the invalidated homohexamer structure. |
| GO:0032991 protein-containing complex | ISS GO_REF:0000024 | ACCEPT | Summary: CAPN3 associates with muscle protein complexes. Reason: Focused mouse triad and SR experiments support co-complex association of CAPN3 with muscle components. The broad protein-containing-complex term is reasonable without assigning a named stoichiometric assembly or requiring direct binding to every co-immunoprecipitated partner. This does not invoke the invalidated homohexamer structure. |
| GO:0033234 negative regulation of protein sumoylation | IDA PMID:20694146 Calpain 3 is a rapid-action, unidirectional proteolytic swit... | KEEP AS NON CORE | Summary: CAPN3 can reduce SUMO conjugation through PIAS proteolysis. Reason: Active human CAPN3 cleaves selected PIAS proteins and reduces PIAS3/SUMO2-associated conjugation in the full primary study, with supportive patient staining in a limited subset. This is a context-dependent regulatory consequence of proteolysis, not a SUMO deconjugating activity or a universal reduction of all SUMO modifications. Supporting Evidence: |
| GO:0043066 negative regulation of apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: CAPN3 supports antiapoptotic signaling in the muscle context. Reason: The human patient-muscle study links CAPN3 to NF-kappaB-dependent c-FLIP expression and cell survival. This supports the existing antiapoptotic process without making CAPN3 intrinsically antiapoptotic in all cells. The IBA target descendant is valid evidence, not circularity; the actual ancestral placement was not reconstructed. Proapoptotic melanoma-variant correlations do not automatically contradict this muscle-specific regulation. Supporting Evidence: |
| GO:0043066 negative regulation of apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CAPN3 supports antiapoptotic signaling in the muscle context. Reason: The human patient-muscle study links CAPN3 to NF-kappaB-dependent c-FLIP expression and cell survival. This supports the existing antiapoptotic process without making CAPN3 intrinsically antiapoptotic in all cells. The IBA target descendant is valid evidence, not circularity; the actual ancestral placement was not reconstructed. Proapoptotic melanoma-variant correlations do not automatically contradict this muscle-specific regulation. Supporting Evidence: |
| GO:0043066 negative regulation of apoptotic process | IMP PMID:18073330 NF-kappaB-dependent expression of the antiapoptotic factor c... | KEEP AS NON CORE | Summary: CAPN3 supports antiapoptotic signaling in the muscle context. Reason: The human patient-muscle study links CAPN3 to NF-kappaB-dependent c-FLIP expression and cell survival. This supports the existing antiapoptotic process without making CAPN3 intrinsically antiapoptotic in all cells. The IBA target descendant is valid evidence, not circularity; the actual ancestral placement was not reconstructed. Proapoptotic melanoma-variant correlations do not automatically contradict this muscle-specific regulation. Supporting Evidence: |
| GO:0043122 regulation of canonical NF-kappaB signal transduction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CAPN3 modulates a selective NF-kappaB-associated pathway in muscle. Reason: The original human study finds that cytokine-triggered NF-kappaB DNA-binding activation remains possible in CAPN3-deficient cells, while c-FLIP target expression is CAPN3 dependent and I-kappaB-alpha turnover is not the proposed step. The CARP work supplies a separate proteolytic link. Retain regulation, without describing CAPN3 as an obligatory upstream activator or a DNA-binding transcription factor. |
| GO:0043122 regulation of canonical NF-kappaB signal transduction | IMP PMID:18073330 NF-kappaB-dependent expression of the antiapoptotic factor c... | KEEP AS NON CORE | Summary: CAPN3 modulates a selective NF-kappaB-associated pathway in muscle. Reason: The original human study finds that cytokine-triggered NF-kappaB DNA-binding activation remains possible in CAPN3-deficient cells, while c-FLIP target expression is CAPN3 dependent and I-kappaB-alpha turnover is not the proposed step. The CARP work supplies a separate proteolytic link. Retain regulation, without describing CAPN3 as an obligatory upstream activator or a DNA-binding transcription factor. |
| GO:0045214 sarcomere organization | ISS GO_REF:0000024 | ACCEPT | Summary: CAPN3 contributes to sarcomeric organization and maintenance. Reason: Titin association and protease-dependent redistribution provide a physical and catalytic role, while mouse null/inactive-protease comparisons distinguish muscle structural maintenance from a generic disease-necessity argument. This supports the conserved organization process at its broad level without asserting the precise initial assembly step or a resolved titin-to-triad bridge. |
| GO:0045661 regulation of myoblast differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CAPN3 regulates the balance between differentiating myoblasts and reserve cells. Reason: The mouse C2C12 gain- and loss-of-function experiments alter reserve-cell formation and MyoD protein abundance. Regulation of differentiation is supported as a context-dependent process, rather than direct activation of satellite cells or proof that CAPN3 is a transcription factor. Purified direct MyoD cleavage was not demonstrated in that study. Supporting Evidence: PMID:20139084 decreasing the transcriptional activity of the key myogenic regulator MyoD via proteolysis |
| GO:0045862 positive regulation of proteolysis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CAPN3 expression promotes protein degradation in the mouse myoblast model. Reason: The traced donor study shows faster MyoD turnover after CAPN3 expression, independent of the tested ubiquitin-proteasome determinants. The authors explicitly could not perform a purified direct-digestion assay. Retain the demonstrated promotion of proteolysis as a non-core regulatory result rather than silently upgrading it to a fully resolved direct physiological substrate reaction. Supporting Evidence: |
| GO:0045862 positive regulation of proteolysis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: CAPN3 expression promotes protein degradation in the mouse myoblast model. Reason: The traced donor study shows faster MyoD turnover after CAPN3 expression, independent of the tested ubiquitin-proteasome determinants. The authors explicitly could not perform a purified direct-digestion assay. Retain the demonstrated promotion of proteolysis as a non-core regulatory result rather than silently upgrading it to a fully resolved direct physiological substrate reaction. Supporting Evidence: |
| GO:0045892 negative regulation of DNA-templated transcription | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CAPN3 can reduce MyoD-dependent transcription through protein turnover. Reason: The mouse-cell reporter and protein-turnover experiments support lower MyoD transactivation after CAPN3 expression. This is regulation of transcription through the abundance of a transcription factor, not CAPN3 binding DNA. The effect is tied to the tested myogenic context and does not define a general transcriptional repressor function. Supporting Evidence: |
| GO:0045892 negative regulation of DNA-templated transcription | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: CAPN3 can reduce MyoD-dependent transcription through protein turnover. Reason: The mouse-cell reporter and protein-turnover experiments support lower MyoD transactivation after CAPN3 expression. This is regulation of transcription through the abundance of a transcription factor, not CAPN3 binding DNA. The effect is tied to the tested myogenic context and does not define a general transcriptional repressor function. Supporting Evidence: |
| GO:0045893 positive regulation of DNA-templated transcription | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CAPN3 supports selective NF-kappaB-dependent gene expression. Reason: The human patient-cell work supports CAPN3-dependent c-FLIP expression even when cytokine-induced NF-kappaB DNA-binding activation can occur. This supports context-dependent positive regulation of transcription without making CAPN3 a DNA-binding factor or claiming indiscriminate activation of all NF-kappaB targets. Supporting Evidence: |
| GO:0045893 positive regulation of DNA-templated transcription | IMP PMID:18073330 NF-kappaB-dependent expression of the antiapoptotic factor c... | KEEP AS NON CORE | Summary: CAPN3 supports selective NF-kappaB-dependent gene expression. Reason: The human patient-cell work supports CAPN3-dependent c-FLIP expression even when cytokine-induced NF-kappaB DNA-binding activation can occur. This supports context-dependent positive regulation of transcription without making CAPN3 a DNA-binding factor or claiming indiscriminate activation of all NF-kappaB targets. Supporting Evidence: |
| GO:0046716 muscle cell cellular homeostasis | TAS PMID:19386580 Novel variants of muscle calpain 3 identified in human melan... | ACCEPT | Summary: Muscle-cell homeostasis is independently supported; the melanoma citation is contextual. Reason: The original TAS citation is retained exactly. Its accessible melanoma abstract mentions calpainopathy as background and is not direct evidence of muscle homeostasis. ACCEPT rests on independent CAPN3 catalytic and muscle-adaptation evidence in PMID:9642272 and PMID:20592470, including effects of protease inactivation, rather than on the melanoma experiment. CAPN3 performs proteolytic and organizing work in muscle maintenance; disease necessity alone is not the argument. |
| GO:0051281 positive regulation of release of sequestered calcium ion into cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: CAPN3 supports calcium release from muscle intracellular stores through a nonproteolytic role. Reason: Mouse Capn3-null fibers have impaired release, whereas C129S muscle retains release kinetics and aldolase/triad organization. Alongside physical localization and binding evidence, this supports a structural contribution to release machinery. The human assignment remains an ortholog inference, not a direct human channel-current measurement; CAPN3 does not form the calcium pore and RyR1 cleavage is not required for this interpretation. |
| GO:0051281 positive regulation of release of sequestered calcium ion into cytosol | ISS GO_REF:0000024 | ACCEPT | Summary: CAPN3 supports calcium release from muscle intracellular stores through a nonproteolytic role. Reason: Mouse Capn3-null fibers have impaired release, whereas C129S muscle retains release kinetics and aldolase/triad organization. Alongside physical localization and binding evidence, this supports a structural contribution to release machinery. The human assignment remains an ortholog inference, not a direct human channel-current measurement; CAPN3 does not form the calcium pore and RyR1 cleavage is not required for this interpretation. |
| GO:0051592 response to calcium ion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: CAPN3 undergoes calcium-dependent changes in proteolytic state and localization. Reason: Native muscle and recombinant-core experiments establish calcium-responsive autolysis, with redistribution depending on the extent of processing. This supports the existing response terms as a regulatory context. Physiological muscle calcium transients are not assumed to activate all CAPN3 instantly, and the broad response annotation is not used to assert a separate downstream signaling pathway. |
| GO:0060090 molecular adaptor activity | IEA GO_REF:0000107 | ACCEPT | Summary: Selective binding and nonproteolytic recruitment support a broad molecular-adaptor role in muscle protein complexes. Reason: GO:0060090 describes selective noncovalent interactions that bring molecules together for coordinated function; it does not require a solved ternary structure. PMID:18676612 combines controlled recombinant CAPN3-C129S/aldolase-A binding with selective loss of triad-associated aldolase A in null mouse muscle, while total aldolase and triad GAPDH are retained. PMID:21295580 finds recruitment and calcium release preserved with catalytically inactive CAPN3. Together these support CAPN3-mediated recruitment of aldolase A into a functional protein assembly and the existing ortholog transfer. CAPN3-RyR pull-down/co-IP can be indirect, so neither a direct RyR interface, simultaneous binary contacts, fixed stoichiometry nor a specific titin-to-triad bridge is asserted. |
| GO:0060090 molecular adaptor activity | ISS GO_REF:0000024 | ACCEPT | Summary: Selective binding and nonproteolytic recruitment support a broad molecular-adaptor role in muscle protein complexes. Reason: GO:0060090 describes selective noncovalent interactions that bring molecules together for coordinated function; it does not require a solved ternary structure. PMID:18676612 combines controlled recombinant CAPN3-C129S/aldolase-A binding with selective loss of triad-associated aldolase A in null mouse muscle, while total aldolase and triad GAPDH are retained. PMID:21295580 finds recruitment and calcium release preserved with catalytically inactive CAPN3. Together these support CAPN3-mediated recruitment of aldolase A into a functional protein assembly and the existing ortholog transfer. CAPN3-RyR pull-down/co-IP can be indirect, so neither a direct RyR interface, simultaneous binary contacts, fixed stoichiometry nor a specific titin-to-triad bridge is asserted. |
| GO:0061061 muscle structure development | IEA GO_REF:0000107 | UNDECIDED | Summary: The developmental scope of the broad muscle-structure term needs its specific donor evidence. Reason: The available work supports muscle maintenance, organization and regulation of myoblast cell-state balance. It does not by itself resolve the full donor claim for development of muscle structure, and the precise underlying experiment has not been traced here. Preserve the mouse-derived assertion pending that source rather than treating muscular dystrophy as sufficient proof of a developmental step. |
| GO:0061061 muscle structure development | ISS GO_REF:0000024 | UNDECIDED | Summary: The developmental scope of the broad muscle-structure term needs its specific donor evidence. Reason: The available work supports muscle maintenance, organization and regulation of myoblast cell-state balance. It does not by itself resolve the full donor claim for development of muscle structure, and the precise underlying experiment has not been traced here. Preserve the mouse-derived assertion pending that source rather than treating muscular dystrophy as sufficient proof of a developmental step. |
| GO:0065003 protein-containing complex assembly | IEA GO_REF:0000107 | UNDECIDED | Summary: CAPN3-dependent organization does not yet distinguish new complex assembly from stability. Reason: The traced mouse donor provides physical aldolase interaction and reduced triad aldolase/RyR in null muscle. This exceeds a bare knockout phenotype, but formation versus maintenance of the associated complex was not resolved. The follow-up favors stabilization while leaving the molecular architecture open. Keep the specific assembly process undecided; neither co-immunoprecipitation nor the withdrawn hexamer model supplies the missing assembly step. |
| GO:0065003 protein-containing complex assembly | ISS GO_REF:0000024 | UNDECIDED | Summary: CAPN3-dependent organization does not yet distinguish new complex assembly from stability. Reason: The traced mouse donor provides physical aldolase interaction and reduced triad aldolase/RyR in null muscle. This exceeds a bare knockout phenotype, but formation versus maintenance of the associated complex was not resolved. The follow-up favors stabilization while leaving the molecular architecture open. Keep the specific assembly process undecided; neither co-immunoprecipitation nor the withdrawn hexamer model supplies the missing assembly step. |
| GO:0070315 G1 to G0 transition involved in cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CAPN3 promotes a quiescent reserve-cell population during mouse myoblast differentiation. Reason: The source model distinguishes reversible cell-cycle exit into quiescence from terminal differentiation. CAPN3 gain and loss affect reserve-cell number, MyoD abundance and G0/G1 measures. This supports the G1-to-G0 context as a mouse-derived process, without equating it with proliferation of activated satellite cells or directly measured human regeneration. Supporting Evidence: |
| GO:0071277 cellular response to calcium ion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CAPN3 undergoes calcium-dependent changes in proteolytic state and localization. Reason: Native muscle and recombinant-core experiments establish calcium-responsive autolysis, with redistribution depending on the extent of processing. This supports the existing response terms as a regulatory context. Physiological muscle calcium transients are not assumed to activate all CAPN3 instantly, and the broad response annotation is not used to assert a separate downstream signaling pathway. |
| GO:0071277 cellular response to calcium ion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: CAPN3 undergoes calcium-dependent changes in proteolytic state and localization. Reason: Native muscle and recombinant-core experiments establish calcium-responsive autolysis, with redistribution depending on the extent of processing. This supports the existing response terms as a regulatory context. Physiological muscle calcium transients are not assumed to activate all CAPN3 instantly, and the broad response annotation is not used to assert a separate downstream signaling pathway. |
| GO:0071472 cellular response to salt stress | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ionic effects on CAPN3 autolysis do not adequately establish a cellular response to environmental salt stress. Reason: The official term is a cellular response to altered environmental salt concentration, under osmotic-stress responses. PMID:20460380 measured autolysis in extracts and after monensin or ouabain treatment of mouse myotubes; those drugs perturb ion gradients and also increase intracellular calcium. PMID:37298357 shows that the sodium effect in rat muscle disappears with physiological potassium and is reproduced by potassium-free Tris conditions, whereas human CAPN3 responds to calcium. Calcium-mediated activation could occur downstream of an ionic insult, but these assays do not establish that CAPN3 performs a salt-stress response. Transferring the disputed sodium-enzyme interpretation as this specific process is over-annotation. This does not deny the reported autolysis or exclude nonphysiological sodium binding. |
| GO:0071472 cellular response to salt stress | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Ionic effects on CAPN3 autolysis do not adequately establish a cellular response to environmental salt stress. Reason: The official term is a cellular response to altered environmental salt concentration, under osmotic-stress responses. PMID:20460380 measured autolysis in extracts and after monensin or ouabain treatment of mouse myotubes; those drugs perturb ion gradients and also increase intracellular calcium. PMID:37298357 shows that the sodium effect in rat muscle disappears with physiological potassium and is reproduced by potassium-free Tris conditions, whereas human CAPN3 responds to calcium. Calcium-mediated activation could occur downstream of an ionic insult, but these assays do not establish that CAPN3 performs a salt-stress response. Transferring the disputed sodium-enzyme interpretation as this specific process is over-annotation. This does not deny the reported autolysis or exclude nonphysiological sodium binding. |
| GO:0072657 protein localization to membrane | IEA GO_REF:0000107 | ACCEPT | Summary: CAPN3 supports localization of aldolase A to muscle triad-associated membranes. Reason: The mouse donor study demonstrates physical aldolase-A interaction and loss of its normal triad recruitment in Capn3-null muscle. C129S retains the relevant localization, supporting a nonproteolytic contribution. GO:0072657 includes maintenance at a membrane location, so an unresolved transport route does not invalidate the broad process. This remains an ortholog-supported organizing function, without asserting direct binding to every SR protein. |
| GO:0072657 protein localization to membrane | ISS GO_REF:0000024 | ACCEPT | Summary: CAPN3 supports localization of aldolase A to muscle triad-associated membranes. Reason: The mouse donor study demonstrates physical aldolase-A interaction and loss of its normal triad recruitment in Capn3-null muscle. C129S retains the relevant localization, supporting a nonproteolytic contribution. GO:0072657 includes maintenance at a membrane location, so an unresolved transport route does not invalidate the broad process. This remains an ortholog-supported organizing function, without asserting direct binding to every SR protein. |
| GO:0097264 self proteolysis | IDA PMID:9642272 Functional defects of a muscle-specific calpain, p94, caused... | ACCEPT | Summary: CAPN3 undergoes self proteolysis. Reason: The disease-mutant work separates retained autolysis from lost exogenous-substrate cleavage in some variants. Independent core experiments demonstrate intramolecular processing. This establishes self proteolysis without assuming that every cleavage event has the same activating or inactivating consequence. The separate GO:1990092 calcium-dependent self-proteolysis row is a more specific description of the same general activity; this source parent row is retained for provenance, not counted as another independent function or added to the core as a redundant process. |
| GO:1990092 calcium-dependent self proteolysis | IDA PMID:12482600 The protease core of the muscle-specific calpain, p94, under... | ACCEPT | Summary: Calcium-dependent self proteolysis is directly demonstrated. Reason: The source tests a recombinant 47-kDa protease-core construct containing the relevant insertion and shows calcium-dependent intramolecular autolysis, including active-site and concentration controls. This construct-specific experiment agrees with native human-muscle calcium dependence; it is not generalized to identical processing kinetics for all alternative products. Supporting Evidence: PMID:12482600 Ca2+-dependent autolysis must be an intramolecular event |
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Download this section (compressed HTML)Q: Which native human CAPN3 substrates and cleavage events directly account for muscle maintenance and exercise adaptation, distinct from overexpression or extract-based candidates?
Q: Which direct partners mediate the nonproteolytic SR/triad role, and does CAPN3 assemble a new complex, maintain an existing one, or both?
Q: Can sodium binding be measured directly under controlled calcium and physiological potassium conditions, separately from autolysis and nonspecific ionic perturbation?
Q: How do the five curated alternative products differ in tissue distribution, calcium regulation, localization and substrate access, especially relative to IS1-deleted experimental constructs?
Q: Does CAPN3 regulate adult human satellite-cell reserve-pool renewal, and how is that distinguished from activation out of quiescence?
Q: Which exact donor experiments support the unresolved plasma-membrane, Z-disc, T-tubule, myofibril-assembly and muscle-development annotations listed in the dated donor-row audit in CAPN3-notes.md?
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