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Information on EC 3.4.22.54 - calpain-3 and Organism(s) Homo sapiens and UniProt Accession P20807
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3.4.22.54 calpain-3Specify your search results
Word Map
- 3.4.22.54
- calpains
- dystrophy
- muscular
-
limb-girdle
-
girdle
-
lgmd2a
- limb
-
calpainopathy
- titin
- calpastatin
- myopathy
-
dysferlin
-
tender
-
autolytic
- sarcomere
- mu-calpains
-
sarcoglycans
- myofibrillar
-
telethonin
-
scapular
-
alpha-sarcoglycan
-
merosin
-
autolyzed
-
caveolin-3
-
nebulin
- lumborum
-
m-lines
-
dysferlinopathy
- sarcoglycanopathy
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
capn3, calpain 3, calpain-3, ncl-1, calpain3, muscle calpain, skeletal muscle-specific calpain, muscle-specific calpain, calpain p94, calpain 3 (p94), 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
calcium-activated neutral proteinase 3
-
-
-
-
calpain L3
-
-
-
-
calpain p94
-
-
-
-
CANP 3
-
-
-
-
Cn94
-
-
-
-
muscle-specific calcium-activated neutral protease 3
-
-
-
-
nCL-1
-
-
-
-
p94
p94-calpain
-
-
-
-
p94
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
657407-83-5
-
78990-62-2
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
connectin + H2O
?
p94 binds to connectin at multiple sites including loci in the N2A and PEVK regions of connectin. Functionally, p94-N2A interactions suppress p94 autolysis and protected connectin from proteolysis. Dynamic nature of connectin molecule as a regulatory scaffold of p94 functions
-
-
?
titin + H2O
?
the enzyme binds the C-terminus of titin at recognition motifs [LIMV]X(3,4) [LIMV]X(2)[LIMV][DE] and [LIMV]X(3,4)[LIMVA]X(2)[LIMV][DE]
-
-
?
AHNAK nucleoprotein + H2O
?
-
AHNAK is lost in cells expressing active CAPN3. Conversely, AHNAK accumulates when calpain 3 is defective in skeletal muscle of calpainopathy patients
-
-
?
additional information
?
-
a small in-frame deletion within the protease domain of muscle-specific calpain, p94 causes early-onset limb-girdle muscular dystrophy 2A
-
-
?
additional information
?
-
mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A
-
-
?
additional information
?
-
mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A
-
-
?
additional information
?
-
-
mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A
-
-
?
additional information
?
-
muscular dystrophy caused by mutations in CANP3 is found in patients from all countries examined so far
-
-
?
additional information
?
-
-
muscular dystrophy caused by mutations in CANP3 is found in patients from all countries examined so far
-
-
?
additional information
?
-
two siblings originating from Reunion Island are affected by a limb-girdle muscular dystrophy type 2A and carry the same two mutations in the calpain gene: 946-1 AGtoAA, affecting a splice site, and S744G. They demonstrate the clinical variability possible with calpain-3 mutations
-
-
?
additional information
?
-
autosomal recessive limb girdle muscular dystrophy is a clinically and genetically heterogenous group of diseases involving at least six different loci. Five genes have already been identified: calpain-3 at LGMD2A (15q15), and four members of the sarcoglycan (SG) complex, alpha-SG at LGMD2D (17q21), beta-SG at LGMD2E (4q12), gamma-SG at LGMD2C (13q12), and delta-SG at LGMD2F (5q33-q34). The gene product at LGMD2B (2p13-p16) is still unknown and at least one other gene is still unmapped
-
-
?
additional information
?
-
-
autosomal recessive limb girdle muscular dystrophy is a clinically and genetically heterogenous group of diseases involving at least six different loci. Five genes have already been identified: calpain-3 at LGMD2A (15q15), and four members of the sarcoglycan (SG) complex, alpha-SG at LGMD2D (17q21), beta-SG at LGMD2E (4q12), gamma-SG at LGMD2C (13q12), and delta-SG at LGMD2F (5q33-q34). The gene product at LGMD2B (2p13-p16) is still unknown and at least one other gene is still unmapped
-
-
?
additional information
?
-
limb-girdle muscular dystrophy: epidemiological study in Guipuzcoa, a small mountainous Basque province in northern Spain, finds the highest prevalence rate of LGMD described so far, 69 per million. Genetic studies demonstrate that 38 cases corresponde to the LGMD2A type, due to calpain-3 gene mutations. The particular calpain-3 mutation predominant in Basque chromosomes, exon 22, 2362AGtoTCATCT, has only been rarely found in the rest of the world. The clinical characteristics of the patients with calpain-3 gene mutations. The disease onset is between the ages of 8 and 15 years, in most cases in the pelvic girdle, and the patients become wheelchair-bound between 11 and 28 years after onset
-
-
?
additional information
?
-
limb-girdle muscular dystrophy type 2A is an autosomal recessive disorder characterized mainly by symmetrical and selective atrophy of the proximal limb muscles. It derives from defects in the human CAPN3 gene. 97 distinct pathogenic calpain 3 mutations have been identified. The mutations are distributed along the entire length of the CAPN3 gene
-
-
?
additional information
?
-
-
limb-girdle muscular dystrophy type 2A is an autosomal recessive disorder characterized mainly by symmetrical and selective atrophy of the proximal limb muscles. It derives from defects in the human CAPN3 gene. 97 distinct pathogenic calpain 3 mutations have been identified. The mutations are distributed along the entire length of the CAPN3 gene
-
-
?
additional information
?
-
p94 is involved in regulation of the eukaryote protein synthesis system
-
-
?
additional information
?
-
p94 proteolytic activity is involved in responses to muscle conditions, p94 inactivation causes limb-girdle muscular dystrophy
-
-
?
cyclin A + H2O
additional information
-
-
calpain 3-mediated cleavage of cyclin A in dividing myeloid pregenitor cells is important for the onset of differentiation
production of a truncated product that lacks the N-terminal destruction box required for its degradation at the end of mitosis. The cleaved form of cyclin A retains the cyclin-dependent kinase binding domain and forms active complexes with cdk2
?
additional information
?
-
-
limb-girdle muscular dystrophy type 2A is an autosomal recessive disorder characterized by selective atrophy of the proximal limb muscles. Its occurence is correlated, in a large number of patients, with defects ihn the human CAP3 gene. The most calpain 3 missense mutations are clustered in three areas that appear to affect intramolecular domain interactions and may impair the assembly and activation of this multi-domain protein
-
-
?
additional information
?
-
-
the selective distribution of the enzyme in T-lymphocytes, B-lymphocytes and natural killer cells , might be related to a specific function of this protease isoform in cells involved in the immune response
-
-
?
additional information
?
-
-
loss-of-function mutations in the calpain 3 gene are associated with limb-girdle muscular dystrophy type 2A. Through the absence of cleavage of the cytoskeletal proteins, calpain 3 deficiency leads to abnormal sarcomers, impairment of muscle contractile capacity and death of muscle fibers
-
-
?
additional information
?
-
-
cytoskeletal proteins are one class of its substrates
-
-
?
additional information
?
-
-
NF-kappaB-dependent expression of the antiapoptotic factor c-FLIP is regulated by calpain 3
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
connectin + H2O
?
p94 binds to connectin at multiple sites including loci in the N2A and PEVK regions of connectin. Functionally, p94-N2A interactions suppress p94 autolysis and protected connectin from proteolysis. Dynamic nature of connectin molecule as a regulatory scaffold of p94 functions
-
-
?
titin + H2O
?
the enzyme binds the C-terminus of titin at recognition motifs [LIMV]X(3,4) [LIMV]X(2)[LIMV][DE] and [LIMV]X(3,4)[LIMVA]X(2)[LIMV][DE]
-
-
?
AHNAK nucleoprotein + H2O
?
-
AHNAK is lost in cells expressing active CAPN3. Conversely, AHNAK accumulates when calpain 3 is defective in skeletal muscle of calpainopathy patients
-
-
?
additional information
?
-
a small in-frame deletion within the protease domain of muscle-specific calpain, p94 causes early-onset limb-girdle muscular dystrophy 2A
-
-
?
additional information
?
-
mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A
-
-
?
additional information
?
-
mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A
-
-
?
additional information
?
-
-
mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A
-
-
?
additional information
?
-
muscular dystrophy caused by mutations in CANP3 is found in patients from all countries examined so far
-
-
?
additional information
?
-
-
muscular dystrophy caused by mutations in CANP3 is found in patients from all countries examined so far
-
-
?
additional information
?
-
two siblings originating from Reunion Island are affected by a limb-girdle muscular dystrophy type 2A and carry the same two mutations in the calpain gene: 946-1 AGtoAA, affecting a splice site, and S744G. They demonstrate the clinical variability possible with calpain-3 mutations
-
-
?
additional information
?
-
autosomal recessive limb girdle muscular dystrophy is a clinically and genetically heterogenous group of diseases involving at least six different loci. Five genes have already been identified: calpain-3 at LGMD2A (15q15), and four members of the sarcoglycan (SG) complex, alpha-SG at LGMD2D (17q21), beta-SG at LGMD2E (4q12), gamma-SG at LGMD2C (13q12), and delta-SG at LGMD2F (5q33-q34). The gene product at LGMD2B (2p13-p16) is still unknown and at least one other gene is still unmapped
-
-
?
additional information
?
-
-
autosomal recessive limb girdle muscular dystrophy is a clinically and genetically heterogenous group of diseases involving at least six different loci. Five genes have already been identified: calpain-3 at LGMD2A (15q15), and four members of the sarcoglycan (SG) complex, alpha-SG at LGMD2D (17q21), beta-SG at LGMD2E (4q12), gamma-SG at LGMD2C (13q12), and delta-SG at LGMD2F (5q33-q34). The gene product at LGMD2B (2p13-p16) is still unknown and at least one other gene is still unmapped
-
-
?
additional information
?
-
limb-girdle muscular dystrophy: epidemiological study in Guipuzcoa, a small mountainous Basque province in northern Spain, finds the highest prevalence rate of LGMD described so far, 69 per million. Genetic studies demonstrate that 38 cases corresponde to the LGMD2A type, due to calpain-3 gene mutations. The particular calpain-3 mutation predominant in Basque chromosomes, exon 22, 2362AGtoTCATCT, has only been rarely found in the rest of the world. The clinical characteristics of the patients with calpain-3 gene mutations. The disease onset is between the ages of 8 and 15 years, in most cases in the pelvic girdle, and the patients become wheelchair-bound between 11 and 28 years after onset
-
-
?
additional information
?
-
limb-girdle muscular dystrophy type 2A is an autosomal recessive disorder characterized mainly by symmetrical and selective atrophy of the proximal limb muscles. It derives from defects in the human CAPN3 gene. 97 distinct pathogenic calpain 3 mutations have been identified. The mutations are distributed along the entire length of the CAPN3 gene
-
-
?
additional information
?
-
-
limb-girdle muscular dystrophy type 2A is an autosomal recessive disorder characterized mainly by symmetrical and selective atrophy of the proximal limb muscles. It derives from defects in the human CAPN3 gene. 97 distinct pathogenic calpain 3 mutations have been identified. The mutations are distributed along the entire length of the CAPN3 gene
-
-
?
additional information
?
-
p94 is involved in regulation of the eukaryote protein synthesis system
-
-
?
additional information
?
-
p94 proteolytic activity is involved in responses to muscle conditions, p94 inactivation causes limb-girdle muscular dystrophy
-
-
?
cyclin A + H2O
additional information
-
-
calpain 3-mediated cleavage of cyclin A in dividing myeloid pregenitor cells is important for the onset of differentiation
production of a truncated product that lacks the N-terminal destruction box required for its degradation at the end of mitosis. The cleaved form of cyclin A retains the cyclin-dependent kinase binding domain and forms active complexes with cdk2
?
additional information
?
-
-
limb-girdle muscular dystrophy type 2A is an autosomal recessive disorder characterized by selective atrophy of the proximal limb muscles. Its occurence is correlated, in a large number of patients, with defects ihn the human CAP3 gene. The most calpain 3 missense mutations are clustered in three areas that appear to affect intramolecular domain interactions and may impair the assembly and activation of this multi-domain protein
-
-
?
additional information
?
-
-
the selective distribution of the enzyme in T-lymphocytes, B-lymphocytes and natural killer cells , might be related to a specific function of this protease isoform in cells involved in the immune response
-
-
?
additional information
?
-
-
loss-of-function mutations in the calpain 3 gene are associated with limb-girdle muscular dystrophy type 2A. Through the absence of cleavage of the cytoskeletal proteins, calpain 3 deficiency leads to abnormal sarcomers, impairment of muscle contractile capacity and death of muscle fibers
-
-
?
additional information
?
-
-
NF-kappaB-dependent expression of the antiapoptotic factor c-FLIP is regulated by calpain 3
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
Ca2+
Ca2+
regulated by Ca2+, contains 2 EF-hand calcium-binding domains. Activated by micromolar concentrations of calcium
Ca2+
-
P94 insertion sequence 1 is a propeptide that must be autoproteolytically cleaved to provide access of substrates and inhibitors to the enzyme's active site. Initial autoproteolytic cleavage is an intramolecular reaction, transient binding of two Ca2+ ions to the core would be sufficient to promote the reaction that is facilitated by having the scissile peptide close to the active site cysteine. The second autolytic cleavage is much slower and requires higher Ca2+ levels, consistent with it being an intermolecular reaction. High increase in hydrolysis rate when Ca2+ is increased from 10 to 100 mM
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
644012, 649012, 649015, 649018, 649019, 649020, 649021, 649022, 649023, 649024, 649025, 663960, 680587, 680771, 697687, 717589, 731896, 732672, 752852, 753363, 754170, 755000, 755076
SwissProt
alternative splicing: I: isoform ID P20807-1, this is the isoform sequence displayed in this entry. II: isoform IDP20807-2, features which should be applied to build the isoform sequence: VSP_005227, VSP_005228. III: isoform ID P20807-3, features which should be applied to build the isoform sequence: VSP_005229. IV: isoform ID P20807-4, features which should be applied to build the isoform sequence: VSP_007813
SwissProt
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
alternatively exon-spliced isoforms of calpain 3 expressed in human leukocytes
two novel splicing variants (hMp78 and hMp84) of calpain-3 gene (CAPN3) have a significant lower expression in vertical growth phase melanomas and, even lower, in metastases, compared to benign nevi
from quadriceps femoris and the soleus muscles. A series of p94 splice variants is expressed immediately after muscle differentiation and differentially change localization during myofibrillogenesis. Endogenous N-terminal (but not C-terminal) domain of p94 is not only localized in the Z-bands but also directly bound to sarcomeric alpha-actinin. Incorporation of proteolytic N-terminal fragments of p94 into the Z-bands. In myofibrils localization of exogenously expressed p94 shifts from the M-line to N2A as the sarcomere lengthens beyond about 0.0026 and 0.0028 mm for wild-type and protease inactive p94, respectively
-
isolated from LGMD2A patients. CAPN3 intervenes in the regulation of the expression of NF-kappaB-dependent survival genes to prevent apoptosis in skeletal muscle. Deregulations in the NF-kappaB pathway could be part of the mechanism responsible for the muscle wasting resulting from CAPN3 deficiency
additional information
-
activity is almost undetectable in polymorphonuclear cells
mRNA for p94 exists only in skeletal muscle with none detected in other tissues including heart muscle and smooth muscles such as intestine
-
of normal and of patients with limb girdle muscular dystrophy. Screening of calpain-3 autolytic activity in limb girdle muscular dystrophy muscle. Missense mutations localized in calpain-3 domains II and III would impair its autolytic activity, possibly because of the charge variation in the residues involved in internal salt bridges. This would finally result in a reduced sensitivity to Ca2+-ions. The pathogenetic effect of these mutations may be understood in terms of impaired communications between protein interdomains
-
fast-twitch and slow-twitch fibers. In this tissue, calpain 3 localizes at several regions of the sarcomere through binding to the giant protein, titin
-
calpain 3 activity promotes turnover of AHNAK in cell culture and in skeletal muscle
-
fasting and refeeding has no effect on calpain-3 mRNA or protein level
-
the amount of autolyzed calpain-3 is unchanged immediately and 3 h after exercise, but increases markedly (from 16% to 35% of total) 24 h after the exercise, and returns to preexercise levels within 7 days
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
calpain 3 has a central role in the regulation of the important cell fate-governing nuclear factor-kappaB pathway. Calpain 3-mediated cardiac ankyrin repeat protein cleavage strengthens its interaction with titin N2A
physiological function
malfunction
-
loss of CAPN3 is 100% specific for limb-girdle muscular dystrophy 2A
physiological function
-
calpain 3 variants can play a proapoptotic role in melanoma cells and its downregulation, as observed in highly aggressive lesions, can contribute to melanoma progression
malfunction
mutations in calpain 3 underlie limb-girdle muscular dystrophy 2A
malfunction
gene mutations causing CAPN3 defects are responsible for limb-girdle muscular dystrophy type 2A (LGMD2A)
malfunction
limb-girdle muscular dystrophy type 2a arises from mutations in the Ca+-activated intracellular cysteine protease calpain-3
malfunction
loss of calpain-3 (CAPN3) activity leads to limb-girdle muscular dystrophy 2A. Calpain-3 mediates regulation of the Na+-Ca2+ exchanger isoform 3. The loss of regulation of Na+-Ca2+ exchanger isoform 3 (NCX3) by calpain-3 can be implicated in diverse muscular pathologies such as the limb-girdle muscular dystrophy 2A
physiological function
aberrant calpain 3 splicing contributes to the muscle differentiation defects of facioscapulohumeral muscular dystrophy patients
physiological function
proteolytic processing of C-terminal titin by calpain 3 has an important role in normal muscle
physiological function
calpain-3 down-regulation can be regarded as a mechanism contributing to melanoma progression. Overexpression of the calpain-3 splicing variant hMp84 in A375 cells or HT-144 cells causes inhibition of cell proliferation, cell death, and increase of both ROS levels and F2-isoprostanes
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). CAN3_HUMAN
821
0
94254
Swiss-Prot
other Location (Reliability: 5)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
43580
recombinantly expressed domain IV of calpain 3 (p94), equilibrium sedimentation
44000
recombinantly expressed domain IV of calpain 3 (p94), sedimentation velocity analysis
94000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
recombinantly expressed domain IV of calpain 3 (p94) is a stable dimer in solution
homodimer
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
proteolytic modification
insertion sequence IS1 interrupts the protease core and must be cleaved for activation and substrate binding
proteolytic modification
proteolytic modification
-
insertion sequence 1 of muscle-specific calpain acts as an internal propeptide. Autoproteolysis serves to remove insertion sequence 1, making the active site available for hydrolysis of exogenous substrates and accessible to inhibitors
proteolytic modification
-
P94 insertion sequence 1 is a propeptide that must be autoproteolytically cleaved to provide access of substrates and inhibitors to the enzyme's active site
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
hanging-drop vapor diffusion method at 22°C, structures of calpain-3 Protease core mutant-C129S, calpain-3 protease core in complex with E-64, calpain-3 protease core in complex with leupeptin
model of calpain 3 by crystal structures of human calpain2 and calpastatin-inhibited rat calpain2
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C129S
additional information
additional information
a small in-frame deletion within the protease domain of muscle-specific calpain, p94 causes early-onset limb-girdle muscular dystrophy 2A
additional information
two siblings originating from Reunion Island are affected by a limb-girdle muscular dystrophy type 2A and carry the same two mutations in the calpain gene: 946-1 AGtoAA, affecting a splice site, and S744G. They demonstrate the clinical variability possible with calpain-3 mutations
additional information
genetic features of 7 patients with limb-girdle muscular dystrophy type 2A from three Japanese families. In two families, an identical G to C mutation at position 1080 the in calpain 3 gene is identified, and a frameshift mutation 1796insA is found in the third family. The former mutation results in a W360R substitution in the proteolytic site of calpain 3, and the latter in a deletion of the Ca2+-binding domain
additional information
-
genetic features of 7 patients with limb-girdle muscular dystrophy type 2A from three Japanese families. In two families, an identical G to C mutation at position 1080 the in calpain 3 gene is identified, and a frameshift mutation 1796insA is found in the third family. The former mutation results in a W360R substitution in the proteolytic site of calpain 3, and the latter in a deletion of the Ca2+-binding domain
additional information
limb-girdle muscular dystrophy: epidemiological study in Guipuzcoa, a small mountainous Basque province in northern Spain, finds the highest prevalence rate of LGMD described so far, 69 per million. Genetic studies demonstrates that 38 cases correspond to the LGMD2A type, due to calpain-3 gene mutations. The particular calpain-3 mutation predominant in Basque chromosomes, exon 22, 2362AGtoTCATCT, has only been rarely found in the rest of the world
additional information
-
the C-terminally truncated form of the enzyme that comprises the protease core, domains I and II, alone with its insertion sequence, IS1, and N-terminal leader sequence, NS. This 47000 Da p94I-II minicalpain is stable during purification
additional information
-
identification of 105 different mutations in calpain 3 gene of patients with limb-girdle muscular dystrophy type 2A. The most frequent mutation is 2362AG->TCATCT (exon 22), which is present in 30.7% of the chromosomes analysed. Other recurrent mutations described are N50S,550DELTA1, G222R, IVS6-1G->A, A483D, IVS17 + 1G->T, 2069-2070DELTAAC, R748Q and R748X, each of which are found in more than 5 chromosomes (of 146). Genotype-phenotype correlation
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
calpain-3 undergoes extremely rapid and exhaustive autolysis. Autolyzed fragments spontaneously associate each other to reconstitute the proteolytic activity. These unique properties of CAPN3 are dependent on IS1 and IS2, two CAPN3-characterizing sequences that do not exist in other calpains or any other proteases. Amino acid sequence alignment of representative vertebrate CAPN3s are carried out
isolation of the intact 94000 Da enzyme is difficult to achieve due to its rapid autolysis. The C-terminally truncated form of the enzyme that comprises the protease core, domains I and II, alone with its insertion sequence, IS1, and N-terminal leader sequence, NS. This 47000 Da p94I-II minicalpain is stable during purification. In the presence of Ca2+, p94I-II cleaves itself within the NS and IS1 sequences. Autolysis is an intramolecular event
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
the C-terminally truncated form of the enzyme that comprises the protease cor, domains I and II, alone with its insertion sequence, IS1, and N-terminal leader sequence, NS is expressed in Escherichia coli BL21(DE3)
-
the His6-tagged PEF domain of calpain 3 coexpressed with the PEF domain of the small subunit that has been tagged with an antifreeze protein is expressed in Escherichia coli BL21(DE3) cells
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
alternative splicing isoform of calpain 3 is increased in facioscapulohumeral muscular dystrophy patients
among melanocytic lesions, the expression of the splicing variants of calpain 3 (Mp78 and Mp84) are significantly downregulated
-
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Boeckmann, B.; Bairoch, A.; Apweiler, R.; Blatter, M.C.; Estreicher, A.; Gasteiger, E.; Martin M.J.; Michoud, K.; O'Donovan, C.; Phan, I.; Pilbout, S.; Schneider, M.
The SWISS-PROT protein knowledgebase and its supplement TrEMBL
Nucleic Acids Res.
31
365-370
2003
Bos taurus (P51186), Homo sapiens (P20807), Mus musculus (Q64691), Sus scrofa (P43368)
Strausberg R.L.; Feingold E.A.; Grouse L.H.; Derge J.G.; et al.
Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences
Proc. Natl. Acad. Sci. USA
99
16899-16903
2002
Homo sapiens (P20807)
Sorimachi H.; Imajoh-Ohmi S.; Emori Y.; Kawasaki H.; Ohno S.; Minami Y.; Suzuki K.
Molecular cloning of a novel mammalian calcium-dependent protease distinct from both m- and mu-types. Specific expression of the mRNA in skeletal muscle
J. Biol. Chem.
264
20106-20111
1989
Homo sapiens (P20807), Rattus norvegicus (P16259)
Richard, I.; Brenguier, L.; Dincer P.; et al.
Multiple independent molecular etiology for limb-girdle muscular dystrophy type 2A patients from various geographical origins
Am. J. Hum. Genet.
60
1128-1138
1997
Homo sapiens (P20807), Homo sapiens, Sus scrofa (P43368)
Richard, I.; Roudaut, C.; Saenz, A.; Pogue, R.; et al.
Calpainopathy - a survey of mutations and polymorphisms
Am. J. Hum. Genet.
64
1524-1540
1999
Homo sapiens (P20807), Homo sapiens
Fardeau, M.; Hillaire, D.; Mignard, C.; Feingold, N.; Feingold, J.; Mignard, D.; de Ubeda, B.; Collin, H.; Tome, F.M.S.; Richard, I.; Beckmann J.S.
Juvenile limb-girdle muscular dystrophy. Clinical, histopathological and genetic data from a small community living in the Reunion island
Brain
119
295-308
1996
Homo sapiens (P20807)
-
Richard, I.; Broux, O.; Allamand, V.; et al.
Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A
Cell
81
27-40
1995
Homo sapiens (P20807), Homo sapiens
Dincer, P.; Leturcq, F.; Richard, I.; et.al.
A biochemical, genetic, and clinical survey of autosomal recessive limb girdle muscular dystrophies in Turkey
Ann. Neurol.
42
222-229
1997
Homo sapiens (P20807), Homo sapiens
Urtasun, M.; Saenz, A.; Roudaut, C.; et al.
Limb-girdle muscular dystrophy in Guipuzcoa (Basque Country, Spain)
Brain
121
1735-1747
1998
Homo sapiens (P20807)
-
Haeffner, K.; Speer, A.; Huebner, C.; Voit, T.; Oexle, K.
A small in-frame deletion within the protease domain of muscle-specific calpain, p94 causes early-onset limb-girdle muscular dystrophy 2A
Hum. Mutat.
1
S298-S300
1998
Homo sapiens (P20807)
-
Penisson-Besnier, I.; Richard, I.; Dubas, F.; Beckmann, J.S.; Fardeau, M.
Pseudometabolic expression and phenotypic variability of calpain deficiency in two siblings
Muscle Nerve
21
1078-1080
1998
Homo sapiens (P20807)
Kawai, H.; Akaike, M.; Kunishige, M.; et al.
Clinical, pathological, and genetic features of limb-girdle muscular dystrophy type 2A with new calpain 3 gene mutations in seven patients from three Japanese families
Muscle Nerve
21
1493-1501
1998
Homo sapiens (P20807), Homo sapiens
de Tullio, R.; Stifanese, R.; Salamino, F.; Pontremoli, S.; Melloni, E.
Characterization of a new p94-like calpain form in human lymphocytes
Biochem. J.
375
689-696
2003
Homo sapiens
Jia, Z.; Petrounevitch, V.; Wong, A.; Moldoveanu, T.; Davies, P.L.; Elce, J.S.; Beckmann, J.S.
Mutations in calpain 3 associated with limb girdle muscular dystrophy: analysis by molecular modeling and by mutation in m-calpain
Biophys. J.
80
2590-2596
2001
Homo sapiens
Rey, M.A.; Davies, P.L.
The protease core of the muscle-specific calpain, p94, undergoes Ca2+-dependent intramolecular autolysis
FEBS Lett.
532
401-406
2002
Homo sapiens
Sorimachi, H.; Saido, T.C.; Suzuki, K.
New era of calpain research. Discovery of tissue-specific calpains
FEBS Lett.
343
1-5
1994
Gallus gallus, Homo sapiens, Rattus norvegicus
Welm, A.L.; Timchenko, N.A.; Ono, Y.; Sorimachi, H.; Radomska, H.S.; Tenen, D.G.; Lekstrom-Himes, J.; Darlington, G.J.
C/EBPalpha is required for proteolytic cleavage of cyclin A by calpain 3 in myeloid precursor cells
J. Biol. Chem.
277
33848-33856
2002
Homo sapiens, Mus musculus
Murphy, R.M.; Snow, R.J.; Lamb, G.D.
m-Calpain and calpain-3 are not autolyzed with exhaustive exercise in humans
Am. J. Physiol.
290
C116-C122
2006
Homo sapiens, Rattus norvegicus
Ravulapalli, R.; Diaz, B.G.; Campbell, R.L.; Davies, P.L.
Homodimerization of calpain 3 penta-EF-hand domain
Biochem. J.
388
585-591
2005
Homo sapiens (P20807)
Garcia Diaz, B.E.; Gauthier, S.; Davies, P.L.
Ca2+ dependency of calpain 3 (p84) activation
Biochemistry
45
3714-3722
2006
Homo sapiens
Saenz, A.; Leturcq, F.; et.al.
LGMD2A: genotype-phenotype correlations based on a large mutational survey on the calpain 3 gene
Brain
128
732-742
2005
Homo sapiens
Duguez, S.; Bartoli, M.; Richard, I.
Calpain 3: a key regulator of the sarcomere?
FEBS J.
273
3427-3436
2006
Homo sapiens
Diaz, B.G.; Moldoveanu, T.; Kuiper, M.J.; Campbell, R.L.; Davies, P.L.
Insertion sequence 1 of muscle-specific calpain p94, acts as an internal propeptide
J. Biol. Chem.
279
27656-27666
2004
Homo sapiens
Fanin, M.; Nascimbeni, A.C.; Angelini, C.
Screening of calpain-3 autolytic activity in LGMD muscle: a functional map of CAPN3 gene mutations
J. Med. Genet.
44
38-43
2007
Homo sapiens
Norton, L.; Parr, T.; Bardsley, R.G.; Ye, H.; Tsintzas, K.
Characterization of GLUT4 and calpain expression in healthy human skeletal muscle during fasting and refeeding
Acta Physiol. (Oxf.)
189
233-240
2007
Homo sapiens
Ono, Y.; Hayashi, C.; Doi, N.; Kitamura, F.; Shindo, M.; Kudo, K.; Tsubata, T.; Yanagida, M.; Sorimachi, H.
Comprehensive survey of p94/calpain 3 substrates by comparative proteomics - possible regulation of protein synthesis by p94
Biotechnol. J.
2
565-576
2007
Homo sapiens (P20807)
Benayoun, B.; Baghdiguian, S.; Lajmanovich, A.; Bartoli, M.; Daniele, N.; Gicquel, E.; Bourg, N.; Raynaud, F.; Pasquier, M.A.; Suel, L.; Lochmuller, H.; Lefranc, G.; Richard, I.
NF-{kappa}B-dependent expression of the antiapoptotic factor c-FLIP is regulated by calpain 3, the protein involved in limb-girdle muscular dystrophy type 2A
FASEB J.
22
1521-1529
2007
Homo sapiens
Huang, Y.; de Morree, A.; van Remoortere, A.; Bushby, K.; Frants, R.R.; den Dunnen, J.; van der Maarel, S.M.
Calpain 3 is a modulator of the dysferlin protein complex in skeletal muscle
Hum. Mol. Genet.
17
1855-1866
2008
Homo sapiens
Murphy, R.M.; Goodman, C.A.; McKenna, M.J.; Bennie, J.; Leikis, M.; Lamb, G.D.
Calpain-3 is autolyzed and hence activated in human skeletal muscle 24 h following a single bout of eccentric exercise
J. Appl. Physiol.
103
926-931
2007
Homo sapiens
Hayashi, C.; Ono, Y.; Doi, N.; Kitamura, F.; Tagami, M.; Mineki, R.; Arai, T.; Taguchi, H.; Yanagida, M.; Hirner, S.; Labeit, D.; Labeit, S.; Sorimachi, H.
Multiple molecular interactions implicate connectin/titin N2A region as a modulating scaffold for p94/calpain 3 activity in skeletal muscle
J. Biol. Chem.
23
14801-14814
2008
Homo sapiens (P20807), Mus musculus (Q64691)
Ojima, K.; Ono, Y.; Doi, N.; Yoshioka, K.; Kawabata, Y.; Labeit, S.; Sorimachi, H.
Myogenic stage, sarcomere length, and protease activity modulate localization of muscle-specific calpain
J. Biol. Chem.
282
14493-14504
2007
Homo sapiens (P20807), Mus musculus (Q64691)
Garnham, C.; Hanna, R.; Chou, J.; Low, K.; Gourlay, K.; Campbell, R.; Beckmann, J.; Davies, P.
Limb-girdle muscular dystrophy type 2A can result from accelerated autoproteolytic inactivation of calpain 3
Biochemistry
48
3457-3467
2009
Homo sapiens
Vissing, K.; Overgaard, K.; Nedergaard, A.; Fredsted, A.; Schjerling, P.
Effects of concentric and repeated eccentric exercise on muscle damage and calpain-calpastatin gene expression in human skeletal muscle
Eur. J. Appl. Physiol.
103
323-332
2008
Homo sapiens (P20807), Homo sapiens
Blazquez, L.; Azpitarte, M.; Saenz, A.; Goicoechea, M.; Otaegui, D.; Ferrer, X.; Illa, I.; Gutierrez-Rivas, E.; Vilchez, J.J.; Lopez de Munain, A.
Characterization of novel CAPN3 isoforms in white blood cells: an alternative approach for limb-girdle muscular dystrophy 2A diagnosis
Neurogenetics
9
173-182
2008
Homo sapiens
Moretti, D.; Del Bello, B.; Cosci, E.; Biagioli, M.; Miracco, C.; Maellaro, E.
Novel variants of muscle calpain 3 identified in human melanoma cells: cisplatin-induced changes in vitro and differential expression in melanocytic lesions
Carcinogenesis
30
960-967
2009
Homo sapiens
Ravulapalli, R.; Campbell, R.L.; Gauthier, S.Y.; Dhe-Paganon, S.; Davies, P.L.
Distinguishing between calpain heterodimerization and homodimerization
FEBS J.
276
973-982
2009
Homo sapiens
Charlton, R.; Henderson, M.; Richards, J.; Hudson, J.; Straub, V.; Bushby, K.; Barresi, R.
Immunohistochemical analysis of calpain 3: advantages and limitations in diagnosing LGMD2A
Neuromuscul. Disord.
19
449-457
2009
Homo sapiens
Laure, L.; Daniele, N.; Suel, L.; Marchand, S.; Aubert, S.; Bourg, N.; Roudaut, C.; Duguez, S.; Bartoli, M.; Richard, I.
A new pathway encompassing calpain 3 and its newly identified substrate cardiac ankyrin repeat protein is involved in the regulation of the nuclear factor-?B pathway in skeletal muscle
FEBS J.
277
4322-4337
2010
Homo sapiens (P20807)
de Morree, A.; Lutje Hulsik, D.; Impagliazzo, A.; van Haagen, H.H.; de Galan, P.; van Remoortere, A.; t Hoen, P.A.; van Ommen, G.B.; Frants, R.R.; van der Maarel, S.M.
Calpain 3 is a rapid-action, unidirectional proteolytic switch central to muscle remodeling
PLoS ONE
5
e11940
2010
Homo sapiens
Charton, K.; Sarparanta, J.; Vihola, A.; Milic, A.; Jonson, P.H.; Suel, L.; Luque, H.; Boumela, I.; Richard, I.; Udd, B.
CAPN3-mediated processing of C-terminal titin replaced by pathological cleavage in titinopathy
Hum. Mol. Genet.
24
3718-3731
2015
Homo sapiens (P20807), Mus musculus (Q64691)
Pistoni, M.; Shiue, L.; Cline, M.S.; Bortolanza, S.; Neguembor, M.V.; Xynos, A.; Ares, M.; Gabellini, D.
Rbfox1 downregulation and altered calpain 3 splicing by FRG1 in a mouse model of facioscapulohumeral muscular dystrophy (FSHD)
PLoS Genet.
9
e1003186
2013
Homo sapiens (P20807), Homo sapiens, Mus musculus (Q64691), Mus musculus
Ono, Y.; Ojima, K.; Shinkai-Ouchi, F.; Hata, S.; Sorimachi, H.
An eccentric calpain, CAPN3/p94/calpain-3
Biochimie
122
169-187
2016
Homo sapiens (P20807), Homo sapiens
Ono, Y.; Sorimachi, H.
Amino acid sequence alignment of vertebrate CAPN3/calpain-3/p94
Data Brief
5
366-367
2015
Homo sapiens (P20807)
Ye, Q.; Campbell, R.L.; Davies, P.L.
Structures of human calpain-3 protease core with and without bound inhibitor reveal mechanisms of calpain activation
J. Biol. Chem.
293
4056-4070
2018
Homo sapiens (P20807), Homo sapiens
Michel, L.Y.; Hoenderop, J.G.; Bindels, R.J.
Calpain-3-mediated regulation of the Na+-Ca2+ exchanger isoform 3
Pflugers Arch.
468
243-255
2016
Homo sapiens (P20807)
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