Affinage

CAPN3

Calpain-3 · UniProt P20807

Length
821 aa
Mass
94.3 kDa
Annotated
2026-06-09
100 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CAPN3/p94 is a skeletal muscle-enriched, Ca2+-dependent cysteine protease that governs sarcomere assembly, remodeling, and myofibrillar integrity, with loss of its proteolytic function causing limb-girdle muscular dystrophy type 2A (PMID:8486713, PMID:10814721, PMID:15138196). Its defining biochemical property is rapid, exhaustive autolysis driven by the active-site cysteine C129 and its calpain-unique insertion sequences: IS1 acts as an internal autoinhibitory propeptide whose autoproteolytic removal activates the enzyme, while a cryptic site in IS2 controls fragment disassembly (PMID:8486713, PMID:15073171, PMID:16627476). Catalysis is strictly Ca2+-dependent—even substoichiometric Ca2+ drives an initial intramolecular cleavage, with a second intermolecular cleavage requiring higher Ca2+—and uniquely also depends on Na+ (PMID:12482600, PMID:16533054, PMID:26363099). CAPN3 binds connectin/titin at multiple sites (N2A, PEVK, M-line, and the alternatively spliced skeletal-muscle C-terminus) through its IS2 region; this interaction stabilizes the enzyme by suppressing autolysis and is integral to its sarcomeric role, and LGMD2A mutations weaken titin binding (PMID:8537379, PMID:9185618, PMID:18310072, PMID:15138196). The enzyme processes titin, calpastatin, MARP2/Ankrd2, and CTBP1 as substrates, is negatively regulated by the scaffold PLEIAD (SIMC1) which also recruits substrates, assembles into a PEF-domain-dependent homotrimer, and can regain activity after autolytic fragmentation via intermolecular complementation (PMID:18310072, PMID:14594950, PMID:23707407, PMID:32200007, PMID:25512505). A nucleolar role cleaving cell-cycle regulators Chk1 and Wee1 has been defined in a zebrafish ortholog (PMID:32588143).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1993 High

    Established the founding paradox of CAPN3 biology—that the protease destroys itself immediately after translation—and pinned this to the active site and the muscle-specific IS2 region.

    Evidence Active-site (C129S/A) and IS2-deletion mutants expressed in COS/L8 cells and in vitro translation

    PMID:8486713

    Open questions at the time
    • Did not resolve whether autolysis is intra- or intermolecular
    • Functional significance of nuclear localization not established
  2. 1995 High

    Identified connectin/titin as a binding partner that stabilizes intact CAPN3, answering how the rapidly self-destructing enzyme could persist in muscle.

    Evidence Yeast two-hybrid of skeletal muscle library and myofibril fractionation localizing intact p94 to the connectin-insoluble fraction

    PMID:8537379

    Open questions at the time
    • Binding shown via IS2 but mechanism of autolysis suppression not defined
    • Number of titin binding sites unknown at this stage
  3. 1997 Medium

    Mapped a C-terminal titin binding site whose tissue-specific alternative splicing restricts CAPN3 anchoring to skeletal muscle.

    Evidence Yeast two-hybrid domain mapping of the connectin C-terminus (M-is7 region)

    PMID:9185618

    Open questions at the time
    • Single-lab Y2H without biochemical confirmation of the complex
    • Functional consequence of C-terminal anchoring not tested
  4. 1998 High

    Defined the multi-step autolytic pathway and localized all cleavage sites to IS1, while showing native CAPN3 forms a homodimer—framing the structural basis of self-processing.

    Evidence Affinity purification of native rabbit p94 and characterization of C129S mutant and autolytic intermediates

    PMID:9794799

    Open questions at the time
    • Relative contribution of intra- vs intermolecular reaction not quantified
    • Oligomeric state later revised to trimer
  5. 1999 Medium

    Demonstrated CAPN3 binds Ca2+ with high affinity and requires it for autolysis even at submicromolar concentrations, establishing Ca2+ as the catalytic trigger.

    Evidence Baculovirus-expressed human p94 with Ca2+ binding and autolysis assays; N-terminal sequencing of fragments (residues 30-31 and 412-413)

    PMID:10068445 PMID:10504417

    Open questions at the time
    • Single-lab in vitro characterization
    • Physiological Ca2+ trigger in muscle not directly demonstrated
  6. 2000 Medium

    Showed in vivo that loss of catalytic activity (or dominant-negative inactive enzyme) is sufficient to produce dystrophic muscle pathology, linking protease function to muscle integrity.

    Evidence Transgenic mice expressing C129S inactive p94 with histological and grip-strength analysis

    PMID:10814721

    Open questions at the time
    • Cannot fully separate dominant-negative accumulation from loss-of-function
    • Specific in vivo substrate driving pathology not identified
  7. 2002 High

    Resolved the initiating autolytic cleavage as intramolecular and concentration-independent, refining the activation mechanism of the protease core.

    Evidence Recombinant protease core with C129S trans-cleavage controls and concentration-dependence assays

    PMID:12482600

    Open questions at the time
    • Later intermolecular steps not addressed here
    • Behavior of full-length enzyme vs isolated core may differ
  8. 2003 High

    Revealed CAPN3 can both resist and degrade calpastatin, positioning it as a regulator of the conventional calpain system, and documented physiologically active splice variants.

    Evidence COS/insect expression of p94delta variant with caseinolytic, autolytic, calpastatin inhibition/cleavage, and FRET assays; biochemical characterization of a PBMC variant

    PMID:12882647 PMID:14594950

    Open questions at the time
    • In vivo relevance of calpastatin cleavage not established
    • Tissue distribution and function of non-muscle variants unclear
  9. 2004 High

    Defined IS1 as an internal autoinhibitory propeptide blocking substrate/inhibitor access, explaining how autoproteolysis activates the enzyme; and showed in a KO mouse that CAPN3 is required for organized sarcomere formation and binds/cleaves titin.

    Evidence Recombinant core mutagenesis with CD, inhibitor titration, and substrate assays; CAPN3 KO mouse EM with in vitro titin binding/cleavage and pathogenic mutant analysis

    PMID:15073171 PMID:15138196

    Open questions at the time
    • Structural model of IS1 occlusion not crystallographically resolved
    • Which titin cleavages are functionally critical in vivo unclear
  10. 2006 High

    Established a two-stage Ca2+-activation model—intramolecular first cleavage at low Ca2+, intermolecular disassembly at higher Ca2+—and showed N2A titin binding suppresses IS2 autolysis and stabilizes fragments.

    Evidence Purified core Ca2+-titration and metal-substitution assays; in vitro autolysis plus yeast Gal4-p94 reporter with disease mutants

    PMID:16533054 PMID:16627476

    Open questions at the time
    • Reporter-based activity readout is indirect
    • How N2A binding mechanically blocks IS2 cleavage not structurally defined
  11. 2007 Medium

    Expanded the CAPN3 substrate landscape beyond conventional calpain targets to translation machinery and glycolytic enzymes via unbiased proteomics.

    Evidence iTRAQ/2-D LC-MALDI comparison of active vs inactive p94 in COS7 cells

    PMID:17373644

    Open questions at the time
    • Individual substrates not independently validated
    • Non-muscle cell context may not reflect physiological cleavage
  12. 2008 High

    Mapped CAPN3 to multiple titin sites (N2A, PEVK, M-line) and uncovered a competitive substrate relationship with MARP2/Ankrd2 at N2A, integrating CAPN3 into a titin-based mechanosignaling node.

    Evidence COS7 co-expression, in vitro proteolysis, competition binding, and mdm-deletion analysis

    PMID:18310072

    Open questions at the time
    • In vivo stoichiometry of competing partners unknown
    • Signaling output downstream of N2A complex not defined
  13. 2013 Medium

    Identified PLEIAD/SIMC1 as a dual regulator that both suppresses CAPN3 autolysis and scaffolds substrate (CTBP1) delivery, adding a non-titin regulatory layer.

    Evidence Reciprocal co-IP, COS7 co-expression, in vitro proteolysis, and CTBP1 cleavage-site mapping

    PMID:23707407

    Open questions at the time
    • Single-lab evidence
    • Physiological setting where PLEIAD-CAPN3-CTBP1 axis operates not established
  14. 2014 High

    Demonstrated intermolecular complementation (iMOC): autolytic N- and C-terminal fragments and even two different inactive mutants can reconstitute active protease, redefining post-autolytic CAPN3 as functional rather than spent.

    Evidence In vitro reconstitution of purified autolytic fragments and active-site mutant complementation

    PMID:25512505

    Open questions at the time
    • In vivo occurrence and prevalence of iMOC unknown
    • Implications for genotype-phenotype in LGMD2A compound heterozygotes untested
  15. 2015 High

    Resolved CAPN3 cleavage of M-band titin at defined sites in normal muscle and showed the FINmaj/LGMD2J mutation alters processing without disrupting binding, and synthesized the unique Na+-dependence of CAPN3 activation.

    Evidence In vitro titin cleavage with product sequencing plus tissue western/IF; review synthesis of Na+-dependence and iMOC

    PMID:25877298 PMID:26363099

    Open questions at the time
    • M-band titin loss in TMD/LGMD2J shown independent of CAPN3
    • Molecular basis of Na+-dependence not structurally defined
  16. 2020 High

    Revised the oligomeric state to a PEF-domain-dependent homotrimer (reinforced by the CBSW domain), correcting the earlier dimer model and locating the assembly determinant.

    Evidence Blue native PAGE, chemical cross-linking, sequential IP, and domain-deletion analysis of recombinant CAPN3

    PMID:32200007

    Open questions at the time
    • Functional consequence of trimerization for catalysis not defined
    • Whether trimer assembles on titin in situ unknown
  17. 2021 Medium

    Uncovered a nucleolar, cell-cycle role: DEF recruits CAPN3 to the nucleolus to cleave Chk1 and Wee1 (and p53) and license synchronized cell-cycle re-entry, extending CAPN3 function beyond the sarcomere.

    Evidence Zebrafish capn3b null mutant, partial hepatectomy regeneration model, nuclear-protein MS, and substrate cleavage assays

    PMID:32588143

    Open questions at the time
    • Demonstrated in zebrafish ortholog, not human CAPN3
    • Whether muscle CAPN3 performs an analogous nucleolar function unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of full-length CAPN3 explaining how IS1 autoinhibition, Na+/Ca2+ dependence, titin anchoring, and PEF-domain trimerization are integrated remains unresolved.
  • No experimental atomic structure of intact CAPN3 in the timeline
  • In vivo substrate hierarchy driving LGMD2A pathology not defined
  • Physiological trigger and tissue context of Na+ co-dependence unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0008092 cytoskeletal protein binding 3 GO:0016787 hydrolase activity 3
Localization
GO:0005856 cytoskeleton 3 GO:0005634 nucleus 1 GO:0005730 nucleolus 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-1643685 Disease 3 R-HSA-397014 Muscle contraction 2
Partners
ANKRD2CASTCHEK1CTBP1SIMC1TTNWEE1
Complex memberships
CAPN3 homotrimerCAPN3-titin/connectin complex

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 p94/CAPN3 undergoes rapid and exhaustive autocatalytic (autolytic) degradation immediately after translation, with the active-site cysteine (C129) required for this process. Mutation of C129 to serine or alanine, or deletion of the p94-specific IS2 region, prevents autolysis and allows stable accumulation of the protein. p94 also shows nuclear localization when expressed in COS cells. COS cell and L8 cell expression of wild-type and deletion/active-site mutant p94; antibody detection; in vitro translation The Journal of biological chemistry High 8486713
1995 p94/CAPN3 binds to connectin/titin through its p94-specific IS2 region (not through the calpain small subunit). The connectin-insoluble fraction of washed myofibrils contains full-length intact p94, suggesting connectin binding stabilizes p94 and regulates its activity. Yeast two-hybrid screening of skeletal muscle library; biochemical fractionation of myofibrils The Journal of biological chemistry High 8537379
1997 p94/CAPN3 binds to the extreme C-terminus of connectin/titin at a region flanked by two IgC2 motifs and the M-is7 intervening sequence. The C-terminal connectin-binding region is tissue-specifically alternatively spliced, with only the skeletal muscle-type (containing M-is7) able to bind p94. Yeast two-hybrid system; C-terminal connectin sequence analysis and binding mapping Archives of biochemistry and biophysics Medium 9185618
1998 Native p94 purified from rabbit skeletal muscle undergoes autolysis in at least three consecutive steps (producing 60 kDa and 58 kDa intermediates before a stable 55 kDa fragment), and the autolysis is partly an intermolecular reaction. All autolysis cleavage sites are located within the p94-specific IS1 region. p94(C129S) purifies as a homodimer. The autolytic site specificity differs from ubiquitous mu- and m-calpains. Antibody-affinity purification of native p94; active-site mutant p94(C129S) expressed in COS cells; biochemical characterization of autolysis products The Biochemical journal High 9794799
1999 Recombinant human p94 expressed in insect (Sf9) cells binds calcium with high affinity and its autolytic activity requires Ca2+; significant autolysis occurs even at submicromolar Ca2+ levels in soluble cell extracts. Baculovirus expression system; Ca2+ binding assays; autolysis assays European journal of biochemistry Medium 10504417
1999 Two autolytic cleavage sites in human CAPN3 were identified by N-terminal sequencing of purified ~55 kDa fragments: cleavage occurs between residues 30–31 (in the NS region) and between residues 412–413 (in the IS1 region). Recombinant CAPN3 expressed in Sf9 insect cells and E. coli; purification by Ni2+ affinity and immunopurification; N-terminal amino acid sequencing of fragments Archives of biochemistry and biophysics Medium 10068445
2000 Transgenic mice expressing catalytically inactive p94 (C129S active-site mutant) develop a myopathy phenotype (decreased grip strength, lobulated and split fibers, centrally placed nuclei) in an age- and expression-dependent manner, demonstrating that loss of p94 protease activity (or dominant-negative accumulation of inactive p94) causes muscle pathology. Transgenic mouse generation; histological analysis of muscle; grip strength measurement Human molecular genetics Medium 10814721
2002 The protease core of p94 (domains I–II plus IS1 and NS; 47 kDa) undergoes Ca2+-dependent intramolecular autolysis. The inactive C129S mutant core was not cleaved by wild-type p94 core in trans, confirming intramolecularity. Autolysis rate was independent of enzyme concentration. Recombinant p94 protease core expression; active-site mutant (C129S); in vitro Ca2+-dependent autolysis assay; concentration-dependence analysis FEBS letters High 12482600
2003 An alternatively spliced variant of p94 (p94delta, lacking IS1, exons 15 and 16) is stably expressed, shows Ca2+-dependent caseinolytic and autolytic activities, but is NOT inhibited by calpastatin; instead, p94delta cleaves calpastatin as a substrate. This positions CAPN3 as a potential regulator of the conventional calpain system by degrading its endogenous inhibitor. COS and insect cell expression of p94delta splice variant; in vitro caseinolytic assay; calpastatin inhibition/cleavage assays; FRET-based activity assay The Journal of biological chemistry High 14594950
2004 IS1 of p94 acts as an internal autoinhibitory propeptide that blocks substrate and inhibitor access to the active site. Autoproteolytic removal of IS1 activates the enzyme. A helix-disrupting mutation (L286P) in IS1 causes premature autoproteolysis. The two autolyzed portions of the core remain tightly associated after IS1 cleavage. Recombinant p94 core expression; deletion and point mutagenesis; exogenous substrate hydrolysis assays; circular dichroism; inhibitor titration (E-64, leupeptin); modeling The Journal of biological chemistry High 15073171
2004 C3/CAPN3 knockout (C3KO) mice show abnormal sarcomere formation: myogenic cells fuse normally in vitro but fail to form well-organized sarcomeres. In vitro studies demonstrated that CAPN3 can bind and cleave titin, and LGMD2A-pathogenic mutations reduce affinity of CAPN3 for titin. CAPN3 knockout mouse generation; electron microscopy of myofibers; in vitro titin-binding and cleavage assays; analysis of pathogenic mutants Human molecular genetics High 15138196
2006 Autolysis of p94/CAPN3 proceeds without immediate disassembly in IS1, but a cryptic autolytic site in IS2 is critical for fragment disassembly. N2A connectin fragment binding to p94 suppresses autolytic disassembly (specifically IS2 autolysis), as shown in a yeast Gal4 transcriptional reporter system. LGMD2A pathogenic missense mutations reduce autolytic activity detectable in this system. In vitro autolysis analysis; yeast Gal4-p94 hybrid transcriptional reporter (beta-galactosidase readout); active-site and disease-mutant analysis The Journal of biological chemistry High 16627476
2006 Strict Ca2+-dependence of p94 protease core activity was established: even substoichiometric Ca2+ promotes intramolecular autoproteolysis (first cleavage), while the second intermolecular cleavage requires higher Ca2+. Na+, K+, and Mg2+ cannot substitute for Ca2+ in catalysis. A two-stage model of p94 core activation is proposed. Purified recombinant p94 core and deletion mutant lacking NS and IS1; in vitro Ca2+-titration autolysis assays; metal ion substitution experiments Biochemistry High 16533054
2007 A comprehensive proteomics survey of p94/CAPN3 substrates in COS7 cells identified novel substrates including components of the protein synthesis system and glycolytic enzymes, in addition to conventional calpain substrates. iTRAQ labeling and 2-D LC-MALDI comparative proteomics in COS7 cells expressing active vs. inactive p94 Biotechnology journal Medium 17373644
2008 p94/CAPN3 binds to connectin/titin at multiple sites including the N2A region, the PEVK region, and the M-line region. p94-N2A interaction suppresses p94 autolysis and protects connectin from proteolysis. MARP2/Ankrd2 competes with p94 for N2A binding and is also cleaved by p94 as a substrate. A titin N2A fragment carrying the mdm (muscular dystrophy with myositis) deletion resists proteolysis and shows weakened MARP binding. COS7 cell co-expression interaction studies; in vitro proteolysis assays; competition binding experiments; analysis of mdm deletion construct The Journal of biological chemistry High 18310072
2013 A novel CAPN3-binding protein PLEIAD (SIMC1/C5orf25) suppresses CAPN3 protease activity (autolysis). PLEIAD also interacts with CTBP1 (a transcriptional co-regulator), and CTBP1 is proteolyzed by CAPN3 in COS7 cells at specific sites. PLEIAD can thus serve both as a CAPN3 suppressor and as a scaffold for CAPN3 substrate recruitment. Co-immunoprecipitation; COS7 cell expression of CAPN3 and PLEIAD; in vitro proteolysis assays; identification of CTBP1 cleavage sites Journal of molecular biology Medium 23707407
2014 CAPN3 protease activity can be reconstituted by intermolecular complementation (iMOC) between its N-terminal and C-terminal autolytic fragments. Active-site mutant CAPN3 activity can be rescued by iMOC with wild-type autolytic fragments, demonstrating that two different CAPN3 mutants can complement each other to restore protease function. Expression and purification of CAPN3 autolytic fragments; in vitro reconstitution of protease activity; complementation assays with active-site mutants Proceedings of the National Academy of Sciences of the United States of America High 25512505
2015 CAPN3 cleaves C-terminal titin (M-band region) at multiple specific sites in vitro, and cleavage products are detectable in normal muscle by western blot and immunofluorescence. The TMD/LGMD2J-causing FINmaj mutation alters this in vitro processing while preserving CAPN3 binding to mutant titin. Pathological loss of M-band titin in TMD/LGMD2J is independent of CAPN3. In vitro CAPN3 cleavage assays with C-terminal titin; protein sequencing of cleavage products; western blot and immunofluorescence of normal and disease muscle Human molecular genetics High 25877298
2020 CAPN3 forms a homotrimer (not merely a homodimer) in native and recombinant preparations, as shown by blue native PAGE, chemical cross-linking, and sequential immunoprecipitation. Trimer formation requires the PEF (penta-EF-hand) domain; the addition of the adjacent CBSW domain to the PEF domain reinforces trimeric assembly. Deletion of the NS, IS1, or IS2 regions does not abolish trimer formation. Blue native PAGE; chemical cross-linking; sequential immunoprecipitation; domain-deletion analysis of recombinant CAPN3 Biochimica et biophysica acta. Proteins and proteomics High 32200007
2021 In zebrafish, CAPN3 (capn3b) is recruited by the nucleolar protein DEF from the cytoplasm to the nucleolus, where it cleaves substrates including p53, Chk1, and Wee1 in a Ca2+-dependent, ubiquitin-proteasome-independent manner. Loss of capn3b causes accumulation of Chk1 and Wee1 in the nucleolus and disrupts synchronized cell cycle re-entry after partial hepatectomy. Zebrafish capn3b null mutant generation; partial hepatectomy model; mass spectrometry of nuclear proteins; demonstration of Chk1 and Wee1 as CAPN3 substrates; nucleolar localization studies Cell regeneration (London, England) Medium 32588143
1996 Antisense oligonucleotide-mediated reduction of p94 expression in differentiating rat myoblasts causes dramatic ultrastructural perturbations in myotubes, particularly affecting myofibrillar stability and Z-line integrity, implicating p94 in myofibrillar maintenance. Antisense oligonucleotide treatment of rat primary myoblast cultures; ultrastructural analysis by electron microscopy Cell growth & differentiation Medium 8930395
2002 Reduction of p94 activity in a muscle cell inducible system results in a significant increase in myogenin levels, suggesting p94 participates in a myogenesis regulatory pathway by modulating myogenic regulatory factors. Inducible expression system in muscle cell line; western blot for myogenin levels Journal of biotechnology Low 12044555
2003 A p94-like CAPN3 splice variant lacking IS1 and exon 15 (a putative nuclear localization signal) is expressed in human peripheral blood mononuclear cells (PBMCs), particularly B- and T-lymphocytes. This variant activates and inactivates without forming the low-Ca2+-requiring form typical of classical calpains, and shows lower sensitivity to calpastatin than ubiquitous calpains. Chromatographic fractionation of PBMC lysates; biochemical characterization of activation kinetics and calpastatin sensitivity; cell-type distribution by expression analysis The Biochemical journal Medium 12882647
2005 Immunohistochemical analysis of single myofibers shows that p94/CAPN3 localizes at the Z-line and N2-line regions of sarcomeres. M-line localization of p94 is influenced by cellular context including contractile status, fiber type, sarcomere maturation, and composition of signal complexes. Immunohistochemistry on isolated single myofibers Journal of muscle research and cell motility Low 16453164
2015 CAPN3 is the first (and only) intracellular enzyme found to depend on Na+ for its activation (in addition to Ca2+), and it is the only protease (other than certain viral proteases) able to regain protease function after autolytic dissociation via intermolecular complementation (iMOC). CAPN3 has both proteolytic and non-proteolytic functions. Review/synthesis of experimental data; Na+-dependence originally established by biochemical assays; iMOC from reconstitution experiments (see PMID 25512505) Biochimie Medium 26363099

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Muscle-specific calpain, p94, responsible for limb girdle muscular dystrophy type 2A, associates with connectin through IS2, a p94-specific sequence. The Journal of biological chemistry 286 8537379
1993 Muscle-specific calpain, p94, is degraded by autolysis immediately after translation, resulting in disappearance from muscle. The Journal of biological chemistry 224 8486713
2004 Null mutation of calpain 3 (p94) in mice causes abnormal sarcomere formation in vivo and in vitro. Human molecular genetics 167 15138196
2005 An autosomal recessive limb girdle muscular dystrophy (LGMD2) with mild mental retardation is allelic to Walker-Warburg syndrome (WWS) caused by a mutation in the POMT1 gene. Neuromuscular disorders : NMD 125 15792865
2004 Muscle MRI findings in patients with limb girdle muscular dystrophy with calpain 3 deficiency (LGMD2A) and early contractures. Neuromuscular disorders : NMD 124 15694138
2005 LGMD2A: genotype-phenotype correlations based on a large mutational survey on the calpain 3 gene. Brain : a journal of neurology 115 15689361
1998 Purification of native p94, a muscle-specific calpain, and characterization of its autolysis. The Biochemical journal 104 9794799
1997 Muscle-specific calpain, p94, interacts with the extreme C-terminal region of connectin, a unique region flanked by two immunoglobulin C2 motifs. Archives of biochemistry and biophysics 102 9185618
1995 The ncl-1 gene and genetic mosaics of Caenorhabditis elegans. Genetics 102 8582642
2008 Multiple molecular interactions implicate the connectin/titin N2A region as a modulating scaffold for p94/calpain 3 activity in skeletal muscle. The Journal of biological chemistry 100 18310072
2004 Molecular diagnosis in LGMD2A: mutation analysis or protein testing? Human mutation 89 15221789
2005 Extensive scanning of the calpain-3 gene broadens the spectrum of LGMD2A phenotypes. Journal of medical genetics 85 16141003
2003 Possible regulation of the conventional calpain system by skeletal muscle-specific calpain, p94/calpain 3. The Journal of biological chemistry 85 14594950
2016 A heterozygous 21-bp deletion in CAPN3 causes dominantly inherited limb girdle muscular dystrophy. Brain : a journal of neurology 82 27259757
2015 An eccentric calpain, CAPN3/p94/calpain-3. Biochimie 82 26363099
2006 CAPN3 mutations in patients with idiopathic eosinophilic myositis. Annals of neurology 78 16607617
1999 Seven autosomal recessive limb-girdle muscular dystrophies in the Brazilian population: from LGMD2A to LGMD2G. American journal of medical genetics 76 10069710
1998 Cloning and expression of mRNA for calpain Lp82 from rat lens: splice variant of p94. Investigative ophthalmology & visual science 76 9478008
1998 ncl-1 is required for the regulation of cell size and ribosomal RNA synthesis in Caenorhabditis elegans. The Journal of cell biology 71 9508766
2016 Natural history of LGMD2A for delineating outcome measures in clinical trials. Annals of clinical and translational neurology 63 27081656
2006 Suppressed disassembly of autolyzing p94/CAPN3 by N2A connectin/titin in a genetic reporter system. The Journal of biological chemistry 61 16627476
1998 Expression of genes (CAPN3, SGCA, SGCB, and TTN) involved in progressive muscular dystrophies during early human development. Genomics 55 9521867
2019 European muscle MRI study in limb girdle muscular dystrophy type R1/2A (LGMDR1/LGMD2A). Journal of neurology 53 31555977
2004 Insertion sequence 1 of muscle-specific calpain, p94, acts as an internal propeptide. The Journal of biological chemistry 52 15073171
1999 Expression, partial purification and functional properties of themuscle-specific calpain isoform p94. European journal of biochemistry 51 10504417
1994 Influence of infection route on the infectivity of baculovirus mutants lacking the apoptosis-inhibiting gene p35 and the adjacent gene p94. Journal of virology 50 8084009
2004 Mutations in Czech LGMD2A patients revealed by analysis of calpain3 mRNA and their phenotypic outcome. Neuromuscular disorders : NMD 49 15351423
2019 Gene Correction of LGMD2A Patient-Specific iPSCs for the Development of Targeted Autologous Cell Therapy. Molecular therapy : the journal of the American Society of Gene Therapy 46 31501033
2007 A third of LGMD2A biopsies have normal calpain 3 proteolytic activity as determined by an in vitro assay. Neuromuscular disorders : NMD 45 17236769
2000 Myopathy phenotype of transgenic mice expressing active site-mutated inactive p94 skeletal muscle-specific calpain, the gene product responsible for limb girdle muscular dystrophy type 2A. Human molecular genetics 45 10814721
2011 Investigation on CAST, CAPN1 and CAPN3 porcine gene polymorphisms and expression in relation to post-mortem calpain activity in muscle and meat quality. Meat science 44 21450414
2003 Characterization of a new p94-like calpain form in human lymphocytes. The Biochemical journal 41 12882647
1992 Sequence comparison among muscle-specific calpain, p94, and calpain subunits. Biochimica et biophysica acta 41 1420333
1997 Mutations in the delta-sarcoglycan gene are a rare cause of autosomal recessive limb-girdle muscular dystrophy (LGMD2). Neurogenetics 40 10735275
2002 The protease core of the muscle-specific calpain, p94, undergoes Ca2+-dependent intramolecular autolysis. FEBS letters 39 12482600
1996 Evidence for implication of muscle-specific calpain (p94) in myofibrillar integrity. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 39 8930395
1995 A primary expression map of the chromosome 15q15 region containing the recessive form of limb-girdle muscular dystrophy (LGMD2A) gene. Human molecular genetics 39 7633422
2015 CAPN3-mediated processing of C-terminal titin replaced by pathological cleavage in titinopathy. Human molecular genetics 38 25877298
2006 Ca2+ dependency of calpain 3 (p94) activation. Biochemistry 38 16533054
2017 Autosomal dominant calpainopathy due to heterozygous CAPN3 C.643_663del21. Muscle & nerve 37 28881388
2010 Synthesis and biological activity of optically active NCL-1, a lysine-specific demethylase 1 selective inhibitor. Bioorganic & medicinal chemistry 37 21227703
2015 A Genetic Cascade of let-7-ncl-1-fib-1 Modulates Nucleolar Size and rRNA Pool in Caenorhabditis elegans. PLoS genetics 36 26492166
2006 Analysis of histopathologic and molecular pathologic findings in Czech LGMD2A patients. Muscle & nerve 36 16372320
2019 Calcium Mechanisms in Limb-Girdle Muscular Dystrophy with CAPN3 Mutations. International journal of molecular sciences 34 31540302
2010 Transcriptional and translational effects of intronic CAPN3 gene mutations. Human mutation 33 20635405
2006 Screening of calpain-3 autolytic activity in LGMD muscle: a functional map of CAPN3 gene mutations. Journal of medical genetics 33 16971480
2001 Different expression patterns for ubiquitous calpains and Capn3 splice variants in monkey ocular tissues. Biochimica et biophysica acta 33 11406271
2008 Characterization of novel CAPN3 isoforms in white blood cells: an alternative approach for limb-girdle muscular dystrophy 2A diagnosis. Neurogenetics 32 18563459
2005 Possible functions of p94 in connectin-mediated signaling pathways in skeletal muscle cells. Journal of muscle research and cell motility 31 16453164
2000 Skeletal muscle-specific calpain, p94, and connectin/titin: their physiological functions and relationship to limb-girdle muscular dystrophy type 2A. Advances in experimental medicine and biology 31 10987085
1996 Mosaic analysis using a ncl-1 (+) extrachromosomal array reveals that lin-31 acts in the Pn.p cells during Caenorhabditis elegans vulval development. Genetics 31 8807292
2009 Identification and association of the single nucleotide polymorphisms in calpain3 (CAPN3) gene with carcass traits in chickens. BMC genetics 30 19265533
1997 Absence of calpain 3 in a form of limb-girdle muscular dystrophy (LGMD2A). Journal of the neurological sciences 30 9077514
2014 The N- and C-terminal autolytic fragments of CAPN3/p94/calpain-3 restore proteolytic activity by intermolecular complementation. Proceedings of the National Academy of Sciences of the United States of America 28 25512505
2003 Newly identified exons encoding novel variants of p94/calpain 3 are expressed ubiquitously and overlap the alpha-glucosidase C gene. FEBS letters 28 14675785
2000 High incidence of 550delA mutation of CAPN3 in LGMD2 patients from Russia. Human mutation 28 10679950
2020 Heterozygous CAPN3 missense variants causing autosomal-dominant calpainopathy in seven unrelated families. Neuropathology and applied neurobiology 27 32896923
2007 Comprehensive survey of p94/calpain 3 substrates by comparative proteomics--possible regulation of protein synthesis by p94. Biotechnology journal 26 17373644
2005 Calpain 3/p94 is not involved in postmortem proteolysis. Journal of animal science 25 15956473
2020 Novel CAPN3 variant associated with an autosomal dominant calpainopathy. Neuropathology and applied neurobiology 24 32342993
2012 Diagnosis by sequencing: correction of misdiagnosis from FSHD2 to LGMD2A by whole-exome analysis. European journal of human genetics : EJHG 23 22378277
2003 The effect of calpain 3 deficiency on the pattern of muscle degeneration in the earliest stages of LGMD2A. Journal of clinical pathology 23 12890817
2021 Systemic delivery of AAVrh74.tMCK.hCAPN3 rescues the phenotype in a mouse model for LGMD2A/R1. Molecular therapy. Methods & clinical development 22 34514031
2013 In vitro correction of a pseudoexon-generating deep intronic mutation in LGMD2A by antisense oligonucleotides and modified small nuclear RNAs. Human mutation 22 23864287
2013 Identification and association of polymorphisms in CAPN1 and CAPN3 candidate genes related to performance and meat quality traits in chickens. Genetics and molecular research : GMR 21 23420372
2013 Impaired regeneration in LGMD2A supported by increased PAX7-positive satellite cell content and muscle-specific microrna dysregulation. Muscle & nerve 21 23553538
2008 cDNA analyses of CAPN3 enhance mutation detection and reveal a low prevalence of LGMD2A patients in Denmark. European journal of human genetics : EJHG 21 18337726
2007 A large deletion and novel point mutations in the calpain 3 gene (CAPN3) in Bulgarian LGMD2A patients. Neurogenetics 21 17318636
2013 PLEIAD/SIMC1/C5orf25, a novel autolysis regulator for a skeletal-muscle-specific calpain, CAPN3, scaffolds a CAPN3 substrate, CTBP1. Journal of molecular biology 20 23707407
1999 Fibre type-specific expression of p94, a skeletal muscle-specific calpain. Journal of muscle research and cell motility 20 10531622
2014 Redox state and mitochondrial respiratory chain function in skeletal muscle of LGMD2A patients. PloS one 19 25079074
2007 Transcriptional explorations of CAPN3 identify novel splicing mutations, a large-sized genomic deletion and evidence for messenger RNA decay. Clinical genetics 19 17979987
2006 Quantitative analysis of CAPN3 transcripts in LGMD2A patients: involvement of nonsense-mediated mRNA decay. Neuromuscular disorders : NMD 19 17157502
2010 Characterisation of capn1, capn2-like, capn3 and capn11 genes in Atlantic halibut (Hippoglossus hippoglossus L.): Transcriptional regulation across tissues and in skeletal muscle at distinct nutritional states. Gene 18 20093171
2020 A muscle-specific calpain, CAPN3, forms a homotrimer. Biochimica et biophysica acta. Proteins and proteomics 17 32200007
2009 Immunohistochemical analysis of calpain 3: advantages and limitations in diagnosing LGMD2A. Neuromuscular disorders : NMD 17 19556129
2020 Splicing impact of deep exonic missense variants in CAPN3 explored systematically by minigene functional assay. Human mutation 15 32668095
2015 The Frequency of c.550delA Mutation of the CANP3 Gene in the Polish LGMD2A Population. Genetic testing and molecular biomarkers 15 26484845
2005 Calpainopathy (LGMD2A) in Croatia: molecular and haplotype analysis. Croatian medical journal 15 16100770
1996 Highly conserved structure in the promoter region of the gene for muscle-specific calpain, p94. Biological chemistry 15 8997499
2020 Capn3 depletion causes Chk1 and Wee1 accumulation and disrupts synchronization of cell cycle reentry during liver regeneration after partial hepatectomy. Cell regeneration (London, England) 14 32588143
2018 CAPN3, DCT, MLANA and TYRP1 are overexpressed in skin of vitiligo vulgaris Mexican patients. Experimental and therapeutic medicine 14 29456684
2022 Targeting the Ubiquitin-Proteasome System in Limb-Girdle Muscular Dystrophy With CAPN3 Mutations. Frontiers in cell and developmental biology 13 35309930
2018 A novel CAPN3 mutation in late-onset limb-girdle muscular dystrophy with early respiratory insufficiency. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 13 29685414
2016 Limb-girdle muscular dystrophy in the Agarwals: Utility of founder mutations in CAPN3 gene. Annals of Indian Academy of Neurology 13 27011640
2011 Does the severity of the LGMD2A phenotype in compound heterozygotes depend on the combination of mutations? Muscle & nerve 13 22006685
2017 FRZB and melusin, overexpressed in LGMD2A, regulate integrin β1D isoform replacement altering myoblast fusion and the integrin-signalling pathway. Expert reviews in molecular medicine 12 28300015
1999 Purification and identification of two putative autolytic sites in human calpain 3 (p94) expressed in heterologous systems. Archives of biochemistry and biophysics 12 10068445
2018 Characteristics of PPT1 and TPP1 enzymes in neuronal ceroid lipofuscinosis (NCL) 1 and 2 by dried blood spots (DBS) and leukocytes and their application to newborn screening. Molecular genetics and metabolism 11 29599076
2010 SNP-array based whole genome homozygosity mapping: a quick and powerful tool to achieve an accurate diagnosis in LGMD2 patients. European journal of medical genetics 11 21172462
2002 Development of an inducible system to assess p94 (CAPN3) function in cultured muscle cells. Journal of biotechnology 11 12044555
2018 Severe limb-girdle muscular dystrophy 2A in two young siblings from Guinea-Bissau associated with a novel null homozygous mutation in CAPN3 gene. Neuromuscular disorders : NMD 10 30415788
2021 Nucleolus-localized Def-CAPN3 protein degradation pathway and its role in cell cycle control and ribosome biogenesis. Journal of genetics and genomics = Yi chuan xue bao 9 34452850
2017 Intravenous and intratumoral injection of Pluronic P94: The effect of administration route on biodistribution and tumor retention. Nanomedicine : nanotechnology, biology, and medicine 9 28535990
2016 Clinical and Pathological Heterogeneity of Korean Patients with CAPN3 Mutations. Yonsei medical journal 9 26632398
2013 Limb-girdle muscular dystrophy type 2a with mutation in CAPN3: the first report in Taiwan. Pediatrics and neonatology 9 23597518
2019 Divergent Features of Mitochondrial Deficiencies in LGMD2A Associated With Novel Calpain-3 Mutations. Journal of neuropathology and experimental neurology 8 30500922
2018 Limb Girdle Muscular Dystrophy due to Digenic Inheritance of DES and CAPN3 Mutations. Case reports in neurology 8 30323756
2014 [A clinicopathological investigation of two autopsy cases of calpainopathy (LGMD2A)]. Brain and nerve = Shinkei kenkyu no shinpo 8 25200581
2004 Bidirectional transcriptional activity of the Pgk1 promoter and transmission ratio distortion in Capn3-deficient mice. Genomics 8 15498466

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