Information on EC 3.4.22.54 - calpain-3

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The expected taxonomic range for this enzyme is: Coelomata

EC NUMBER
COMMENTARY
3.4.22.54
-
RECOMMENDED NAME
GeneOntology No.
calpain-3
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
broad endopeptidase activity
show the reaction diagram
-
-
-
-
broad endopeptidase specificity
show the reaction diagram
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
endopeptidase; peptides, endopeptidase
-
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
C3
-
-
-
-
C3DIV
-
-
calcium-activated neutral proteinase 3
-
-
-
-
calcium-activated neutral proteinase 3
-
-
Calp3
-
-
calpain 3
P51186
-
calpain 3
P20807
-
calpain 3
-
-
calpain 3
-
-
calpain 3 (p94)
-
-
calpain 3 domain IV
-
-
calpain 3/p94
-
-
calpain L3
-
-
-
-
calpain L3
-
-
calpain M
-
an arthropod M-class calpain homologue to Homarus americanus muscle-specific calpain M
calpain p94
-
-
-
-
calpain p94
-
-
calpain p94
-
-
calpain-3
-
-
calpain-3
-
-
calpain3
P51186
-
calpain3
Q92177
-
CANP 3
-
-
-
-
CANP 3
-
-
CAPN3
P51186
-
CAPN3
Q92177
-
Cn94
-
-
-
-
MP78
-
splicing variant
Mp84
-
splicing variant
muscle calpain
-
-
muscle-specific calcium-activated neutral protease 3
-
-
-
-
muscle-specific calcium-activated neutral protease 3
-
-
muscle-specific calpain
-
-
nCL-1
-
-
-
-
p94
-
-
-
-
p94
Q92177
-
p94-calpain
-
-
-
-
p94/calpain 3
P20807
-
p94/calpain 3
-
-
p94/calpain 3
Q64691
-
skeletal muscle-specific calpain
-
-
CAS REGISTRY NUMBER
COMMENTARY
657407-83-5
-
78990-62-2
-
ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
breeds Brahmna, Belmont REd, Santa Gertrudis
SwissProt
Manually annotated by BRENDA team
pure line S01, pure line S02, pure line S03, pure line S05, pure line D99, native breed Huiyang Huxu, native breed Qingyuan Ma, native breed Caoke, native breed Shandi Black-bone
SwissProt
Manually annotated by BRENDA team
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
Manually annotated by BRENDA team
expressed in COS-7 cells
SwissProt
Manually annotated by BRENDA team
limb-girdle muscular dystrophy type 2A patients
-
-
Manually annotated by BRENDA team
model of calpain 3 by crystal structures of human calpain2 and calpastatin-inhibited rat calpain2
-
-
Manually annotated by BRENDA team
recombinant
-
-
Manually annotated by BRENDA team
C3KO or wild-type mice
-
-
Manually annotated by BRENDA team
Norway lobster
-
-
Manually annotated by BRENDA team
; lang-Evans hooded rats, male, 6-8 month old
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
malfunction
-
inactivating mutations of the CAPN3 gene, encoding the muscle-specific calpain-3, result in the limb-girdle muscular dystrophy-2A
malfunction
-
mitochondrial abnormalities, energy deficit and oxidative stress are features of calpain 3 deficiency in skeletal muscle
malfunction
-
deficiency in calpain 3 is associated with apoptosis as indicated by increases of caspase 3 activity, the absence of calpain 3 modifies the sarcoplasmic reticulum Ca2+ release, by a decrease of the sarcoplasmic reticulum content, an impairment of ryanodine receptor signalling, and an increase of L-type Ca2+ channel activity
malfunction
-
loss of CAPN3 is 100% specific for limb-girdle muscular dystrophy 2A
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
-
calcium-dependent plasma membrane repair does not require calpain-3
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
physiological function
-
calpain 3-dependent proteolysis plays a role in activating support proteins of intracellular Ca2+ signalling at a stage of cellular differentiation which is crucial for skeletal muscle regeneration
physiological function
-
calpain 3 is involved in the myogenic differentiation process, calpain 3 participates in the establishment of the pool of reserve cells by decreasing the transcriptional activity of the key myogenic regulator MyoD via proteolysis independently of the ubiquitin-proteasome degradation pathway
physiological function
-
the enzyme plays a role in tenderizing connective tissue networks during growth and moulting
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
26S proteasome regulatory subunit 6A + H2O
?
show the reaction diagram
P20807
-
-
-
?
AHNAK nucleoprotein + H2O
?
show the reaction diagram
-
-
-
-
-
AHNAK nucleoprotein + H2O
?
show the reaction diagram
-
AHNAK is lost in cells expressing active CAPN3. Conversely, AHNAK accumulates when calpain 3 is defective in skeletal muscle of calpainopathy patients
-
-
?
AHNAK-N peptide + H2O
?
show the reaction diagram
-
a putative cleavage site is AHNAK-C2.2
-
-
?
aldolase A + H2O
?
show the reaction diagram
-
not an in vivo substrate or not detectable in total cell extracts
-
-
?
alpha-actinin-3 + H2O
?
show the reaction diagram
-
-
-
-
?
alpha-fodrin + H2O
?
show the reaction diagram
-
-
-
-
?
annexin A1 + H2O
?
show the reaction diagram
P20807
-
-
-
?
annexin A2 + H2O
?
show the reaction diagram
P20807
-
-
-
?
annexin A7 + H2O
?
show the reaction diagram
P20807
-
-
-
?
beta-catenin + H2O
?
show the reaction diagram
-
-, calpain 3 specifically controls the level of membrane-associated beta-catenin and M-cadherin during myogenesis
-
-
?
calpastatin + H2O
?
show the reaction diagram
-
-
-
-
?
cardiac ankyrin repeat protein + H2O
?
show the reaction diagram
-
-
-
-
?
connectin + H2O
?
show the reaction diagram
-
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
-
-
?
eukaryotic elongation factor 1-alpha 1 + H2O
?
show the reaction diagram
P20807
-
-
-
?
eukaryotic elongation factor 1-alpha 2 + H2O
?
show the reaction diagram
P20807
-
-
-
?
eukaryotic elongation factor 2 + H2O
?
show the reaction diagram
P20807
-
-
-
?
eukaryotic translation initiation factor 3 subunit 7 + H2O
?
show the reaction diagram
P20807
-
-
-
?
ezrin + H2O
?
show the reaction diagram
-
-
-
-
?
filamin C + H2O
?
show the reaction diagram
-
-
-
-
?
filamin C + H2O
?
show the reaction diagram
-
enzyme specifically cleaves the C-terminal portion
-
-
?
filamin C + H2O
?
show the reaction diagram
-
enzyme specifically cleaves the C-terminal portion in living cells. Filamin C may be an in vivo substrate to c3, functioning to regulate protein-protein interactions with the sarcoglycans
-
-
?
filamin-A + H2O
?
show the reaction diagram
P20807
-
-
-
?
fodrin + H2O
?
show the reaction diagram
-
-
-
-
?
fructose bisphosphatealdolase A + H2O
?
show the reaction diagram
P20807
-
-
-
?
glyceraldehyde-3-phosphate dehydrogenase + H2O
?
show the reaction diagram
P20807
-
-
-
?
HSP60 + H2O
?
show the reaction diagram
-
-
-
-
?
importin-7 + H2O
?
show the reaction diagram
P20807
-
-
-
?
M-cadherin + H2O
?
show the reaction diagram
-
-, calpain 3 specifically controls the level of membrane-associated beta-catenin and M-cadherin during myogenesis
-
-
?
MyoD + H2O
?
show the reaction diagram
-
calpain 3 down-regulates MyoD protein levels
-
-
?
myosin light chain 1 + H2O
?
show the reaction diagram
-
-
-
-
?
p94 + H2O
?
show the reaction diagram
P20807
best substrate for p94 is p94 itself
-
-
?
PIAS3 + H2O
?
show the reaction diagram
-
-
-
-
?
ryanodine receptor + H2O
?
show the reaction diagram
-
-
-
-
?
succinyl-leucine-tyrosine-aminomethylcoumarin + H2O
?
show the reaction diagram
-
-
-
-
?
talin + H2O
?
show the reaction diagram
-
-
-
-
?
thioredoxin + H2O
?
show the reaction diagram
P20807
-
-
-
?
titin + H2O
?
show the reaction diagram
-
-
-
-
?
titin + H2O
?
show the reaction diagram
-
-
-
-
?
titin + H2O
?
show the reaction diagram
-
-
-
-
?
titin + H2O
?
show the reaction diagram
-
-
-
-
?
titin + H2O
?
show the reaction diagram
-
calpain 3 expression is required for normal myofibril formation.calpain 3 may influence the role of titin in sarcomere formation through proteolytic cleavage. The limb girdle muscular dystrophy 2A mutations in calpain C3 influence binding of calpain C3 to titin
-
-
?
triosephosphate isomerase + H2O
?
show the reaction diagram
P20807
-
-
-
?
tropomyosin + H2O
?
show the reaction diagram
-
-
-
-
?
troponin I + H2O
?
show the reaction diagram
-
-
-
-
?
troponins T + H2O
?
show the reaction diagram
-
-
-
-
?
very long chain acyl-coenzyme A dehydrogenase + H2O
?
show the reaction diagram
-
an in vivo substrate for calpain-3
-
-
?
vimentin + H2O
?
show the reaction diagram
P20807
-
-
-
?
vinexin + H2O
?
show the reaction diagram
-
-
-
-
?
cyclin A + H2O
?
show the reaction diagram
-
-
-
-
?
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
?
MARP2/Ankrd2 + H2O
?
show the reaction diagram
-
-
-
-
?
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
?
-
-
the enzyme is associated with limb-girdle muscular dystrophy 2A
-
-
-
additional information
?
-
-
mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A
-
-
-
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
?
-
-
important protein for normal muscle function. Mutations in the c3 gene result in 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
?
-
-
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
?
-
-
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
?
-
-
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
?
-
-
calpain 3/p94 is not involved in postmortem proteolysis
-
-
-
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
?
-
-
neither the reduction of calpain 3 nor its aberrant activity is responsible for the muscular dystrophy with myositis (mdm). Overexpression of calpain 3 exacerbates muscular dystrophy with myositis (mdm)
-
-
-
additional information
?
-
-
skeletal muscle-specific calpain participates in the regulation of the conventional calpain-calpastatin system in skeletal muscle
-
-
-
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
-
-
-
additional information
?
-
P20807
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
-
-
-
additional information
?
-
-
calpain-3 does not cleave acetyl-coenzyme A acyltransferase, carnitine O-palmitoyl transferase II, carnitine acetyltransferase, and trifunctional protein alpha subunit
-
-
-
additional information
?
-
-
calpain 3 does not cleave PIAS4
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
AHNAK nucleoprotein + H2O
?
show the reaction diagram
-
AHNAK is lost in cells expressing active CAPN3. Conversely, AHNAK accumulates when calpain 3 is defective in skeletal muscle of calpainopathy patients
-
-
?
alpha-actinin-3 + H2O
?
show the reaction diagram
-
-
-
-
?
alpha-fodrin + H2O
?
show the reaction diagram
-
-
-
-
?
beta-catenin + H2O
?
show the reaction diagram
-
calpain 3 specifically controls the level of membrane-associated beta-catenin and M-cadherin during myogenesis
-
-
?
filamin C + H2O
?
show the reaction diagram
-
enzyme specifically cleaves the C-terminal portion in living cells. Filamin C may be an in vivo substrate to c3, functioning to regulate protein-protein interactions with the sarcoglycans
-
-
?
M-cadherin + H2O
?
show the reaction diagram
-
calpain 3 specifically controls the level of membrane-associated beta-catenin and M-cadherin during myogenesis
-
-
?
PIAS3 + H2O
?
show the reaction diagram
-
-
-
-
?
ryanodine receptor + H2O
?
show the reaction diagram
-
-
-
-
?
titin + H2O
?
show the reaction diagram
-
-
-
-
?
titin + H2O
?
show the reaction diagram
-
-
-
-
?
titin + H2O
?
show the reaction diagram
-
-
-
-
?
titin + H2O
?
show the reaction diagram
-
calpain 3 expression is required for normal myofibril formation.calpain 3 may influence the role of titin in sarcomere formation through proteolytic cleavage. The limb girdle muscular dystrophy 2A mutations in calpain C3 influence binding of calpain C3 to titin
-
-
?
tropomyosin + H2O
?
show the reaction diagram
-
-
-
-
?
troponin I + H2O
?
show the reaction diagram
-
-
-
-
?
troponins T + H2O
?
show the reaction diagram
-
-
-
-
?
connectin + H2O
?
show the reaction diagram
-
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
-
-
?
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
?
MARP2/Ankrd2 + H2O
?
show the reaction diagram
-
-
-
-
?
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
?
-
-
the enzyme is associated with limb-girdle muscular dystrophy 2A
-
-
-
additional information
?
-
-
mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A
-
-
-
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
?
-
-
important protein for normal muscle function. Mutations in the c3 gene result in 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
?
-
-
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
?
-
-
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
?
-
-
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
?
-
-
calpain 3/p94 is not involved in postmortem proteolysis
-
-
-
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
?
-
-
neither the reduction of calpain 3 nor its aberrant activity is responsible for the muscular dystrophy with myositis (mdm). Overexpression of calpain 3 exacerbates muscular dystrophy with myositis (mdm)
-
-
-
additional information
?
-
-
skeletal muscle-specific calpain participates in the regulation of the conventional calpain-calpastatin system in skeletal muscle
-
-
-
additional information
?
-
-
NF-kappaB-dependent expression of the antiapoptotic factor c-FLIP is regulated by calpain 3
-
-
-
additional information
?
-
P20807
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
-
-
-
additional information
?
-
-
calpain 3 does not cleave PIAS4
-
-
-
METALS and IONS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
Ca2+
-
regulated by Ca2+, contains 2 EF-hand calcium-binding domains. Activated by micromolar concentrations of calcium
Ca2+
P20807
regulated by Ca2+, contains 2 EF-hand calcium-binding domains. Activated by micromolar concentrations of calcium
Ca2+
-
regulated by Ca2+, contains 2 EF-hand calcium-binding domains. Activated by micromolar concentrations of calcium
Ca2+
-
-
Ca2+
P16259
dependent on Ca2+
Ca2+
-
required, K0.5 is between 0.02 and 0.03 mM
Ca2+
-
dependent on
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
Ca2+
-
autolysis of skeletal muscle-specific calpain does not require Ca2+, calpastatinolysis occurs in a Ca2+-dependent manner
Ca2+
-
calcium-dependent protease
Ca2+
-
at less than 50 nM Ca2+ calpain-3 remains nonactivated, at 200 nM Ca2+ calpain-3 becomes active; calpain-3 autolyzes (becoming proteolytically active) in a tightly calcium-dependent manner. It remains in its nonactivated full-length form if [Ca2+] is maintained at up to 50 nM, the normal resting level, even with brief increases to 0.002-0.02 mM during repeated tetanic contractions, but it becomes active (though still bound) if [Ca2+] is kept slightly elevated at 200 nM (about 20% autolysis in 1 h). Calpain-3 does not spontaneously autolyze even when free in solution with 200 nM Ca2+ for up to 60 min
Ca2+
-
submicromolar calcium concentrations necessary
Ca2+
-
required
Ca2+
-
calpain 3 is a calcium-dependent cysteine protease
Ca2+
-
calpain 3/p94 is activated by Ca2+ and undergoes very rapid autolytic degradation even in the absence of Ca2+
Ca2+
-
dependent on
Ca2+
-
dependent on
K+
-
1 mM, moderate increase of hydrolysis rate
Mg2+
-
1 mM, moderate increase of hydrolysis rate
Na+
-
1 mM, moderate increase of hydrolysis rate
Na+
-
calpain 3/p94 is activated by Na+ and undergoes Na+-dependent, but not Cs+-dependent, autolysis in the absence of Ca2+. Na+ and Ca2+ complementarily activate autolysis of calpain3/p94 at physiological concentrations. Na+ and Ca2+ direct calpain3/p94 to proteolyze different substrates
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
calpain inhibitor I
-
IC50: 0.00025 mM
calpain inhibitor II
-
IC50: 0.00025 mM
Calpastatin
-
-
-
Calpastatin
P20807
-
-
Calpastatin
-
-
-
recombinant rat brain calpastatin
-
IC50: 0.0036 mM
-
Leupeptin
-
IC50: 0.002 mM
additional information
-
no inhibition by calpastatin
-
additional information
-
not inhibited by calpastatin
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
additional information
-
aldolase A as binding partner for calpain-3
-
additional information
-
no influence of muscle stretching to activation of calpain-3
-
IC50 VALUE [mM]
IC50 VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.00025
-
calpain inhibitor I
-
IC50: 0.00025 mM
0.00025
-
calpain inhibitor II
-
IC50: 0.00025 mM
0.002
-
Leupeptin
-
IC50: 0.002 mM
0.0036
-
recombinant rat brain calpastatin
-
IC50: 0.0036 mM
-
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
pI VALUE
pI VALUE MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
5.2
-
-
calculated from amino acid sequence
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
-, Q9GLG7
numerous splice variants of Capn3 are expressed, they contain deletionsor insertions in or around the IS1, IS2, and NS regions
Manually annotated by BRENDA team
-
calpain 3 or its isoforms is necessary for formation of the nuclear cataract that is observed in the alpha3Cx46-/- lens. In the absence of the CAPN3 gene, the formation of a cataract is delayed, and its appearance is changed to a more diffuse, pulverulent type
Manually annotated by BRENDA team
P20807
alternatively exon-spliced isoforms of calpain 3 expressed in human leukocytes
Manually annotated by BRENDA team
-
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
Manually annotated by BRENDA team
-
calpain-3 is localized at the skeletal muscle M-line, Z-band, and the N2A region of the large myofibrillar protein, titin
Manually annotated by BRENDA team
-
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
Manually annotated by BRENDA team
-
flexor digitorum brevis
Manually annotated by BRENDA team
-
mRNA level of calpain 3 is highest in the longissimus thoracis et lumborum, followed by semimembranosus, psoas major, and semitendinosus
Manually annotated by BRENDA team
-
mRNA for p94 exists only in skeletal muscle with none detected in other tissues including heart muscle and smooth muscles such as intestine
Manually annotated by BRENDA team
P16259
mRNA for p94 exists only in skeletal muscle with none detected in other tissues including heart muscle and smooth muscles such as intestine
Manually annotated by BRENDA team
-
vastus lateralis
Manually annotated by BRENDA team
-
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
Manually annotated by BRENDA team
-
fasting and refeeding has no effect on calpain-3 mRNA or protein level
Manually annotated by BRENDA team
-
calpain 3 may be involved in the mechanism of exogenous growth hormone action on skeletal muscle growth. Recombinant porcine growth hormone up-regulates mRNA expression of calpain 3 in a muscle type-specific manner, being more remarkable in semitendinosus muscles than in longissimus dorsi
Manually annotated by BRENDA team
-
calpain 3 activity promotes turnover of AHNAK in cell culture and in skeletal muscle
Manually annotated by BRENDA team
-
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
Manually annotated by BRENDA team
-
musculus extensor digitorum longus, musculus soleus; virtually all calpain-3 present in mature muscle fibers is tightly bound in the vicinity of the titin N2A line and triad junctions, most calpain-3 is evidently bound within the contractile filament lattice
Manually annotated by BRENDA team
-
musculus quadriceps
Manually annotated by BRENDA team
-
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
Manually annotated by BRENDA team
-
papillomavirus-associated urothelial tumors of the urinary bladder
Manually annotated by BRENDA team
additional information
-
activity is almost undetectable in polymorphonuclear cells
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
bound to the N2A line on titin or at the triad junctions
Manually annotated by BRENDA team
-
in urothelial cancer cells, calpain 3 is observed mostly in the cytoplasm
Manually annotated by BRENDA team
additional information
-
triad
-
Manually annotated by BRENDA team
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
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
55000
-
-
full-length CAPN3 undergoes almost complete autolysis and runs as a 55 kDa band, SDS-PAGE
65900
-
-
calculated from amino acid sequence
84000
-
-
full-length splice variant Mp84, SDS-PAGE
94000
-
-
-
94000
-
-
full-length, unautolyzed form of calpain-3,SDS-PAGE; Western blot
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
?
P16259
x * 94084, calculation from nucleotide sequence
?
-
x * 94000, SDS-PAGE
dimer
-
recombinantly expressed domain IV of calpain 3 (p94) is a stable dimer in solution
homodimer
-
Ca2+-bound
homodimer
-
-
homodimer
-
calpain 3 domain IV is a homodimer, 2 * 22000, SDS-PAGE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
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
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
Crystallization/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
model of calpain 3 by crystal structures of human calpain2 and calpastatin-inhibited rat calpain2
-
GENERAL STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
15% autolysis after 1 min exposure to 0.0025 mM Ca2+
-
autodigestion with 50% loss of total activity after exposure to 0.1 mM Ca2+
-
enzyme is not autolyzed with exhaustive exercise in humans
-
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
-
rapid autodigestion
-
enzyme is not autolyzed with exhaustive exercise in humans
-
no autolysis after 1 min exposure to 0.0025 mM Ca2+
-
up to 60 min, in presence of 200 nM Ca2+, no spontaneous autolysation
-
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
Ni-NTA column chromatography
-
recombinant
-
recombinantly expressed domain IV
-
DEAE-Toyopearl column chromatography
-
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
cloning of human full-length CDSs in BD Creator(TM) system donor vector
P20807
expressed in NIH-3T3 fibroblasts
-
expression in COS-7 cells
-
expression of domain IV in Escherichia coli BL21 (DE3)
-
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
-
isoforms
-, Q9GLG7
expression in COS-7 cells
-
expression in Eschericia coli
-
COS-7 cells are transfected with C3 construct ssubcloned into pcDNA 3.1 and/or a C-terminal human FLNC construct subcloned into pCMV Tag2B
-
skeletal muscle enzyme
-
EXPRESSION
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
among melanocytic lesions, the expression of the splicing variants of calpain 3 (Mp78 and Mp84) are significantly downregulated
-
reserve cells express higher levels of endogenous Capn3 mRNA than proliferating myoblasts
-
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
A101K
-
limb-girdle muscular dystrophy 2A
A489W
-
limb-girdle muscular dystrophy 2A
A490W
-
limb-girdle muscular dystrophy 2A
A748Q
-
limb-girdle muscular dystrophy 2A
A788S
-
limb-girdle muscular dystrophy 2A
C129S
-
inactive
D268A
-
limb-girdle muscular dystrophy 2A
D665LfsX18
-
limb-girdle muscular dystrophy 2A
E206K
-
limb-girdle muscular dystrophy 2A
F167AfsX29
-
limb-girdle muscular dystrophy 2A
G222A
-
limb-girdle muscular dystrophy 2A
G691WfsX7
-
limb-girdle muscular dystrophy 2A
H690RfsX9
-
limb-girdle muscular dystrophy 2A
K254del
-
limb-girdle muscular dystrophy 2A
K254E
-
limb-girdle muscular dystrophy 2A
K595VfsX70
-
limb-girdle muscular dystrophy 2A
K729VfsX21
-
limb-girdle muscular dystrophy 2A
P637HfsX25
-
limb-girdle muscular dystrophy 2A
Q142X
-
limb-girdle muscular dystrophy 2A
Q565P
-
limb-girdle muscular dystrophy 2A
R437C
-
limb-girdle muscular dystrophy 2A
R490Q
-
limb-girdle muscular dystrophy 2A
R572T
-
limb-girdle muscular dystrophy 2A
R748Q
-
limb-girdle muscular dystrophy 2A
R788SfsX14
-
limb-girdle muscular dystrophy 2A
S260F
-
limb-girdle muscular dystrophy 2A
S479G
-
limb-girdle muscular dystrophy 2A
T139I
-
limb-girdle muscular dystrophy 2A
C129S
-
proteolytically inactive
C129S
-
it is difficult to efficiently express the mutant enzyme C129S
C129S
-
protease-inactive mutant form
N358D
-
activity-attenuated mutant, in contrast to wild type, which autolyses quickly in the absence of Ca2+, the mutant N358D expressed in Sf-9 cells can be partially purified, N358D is very unstable in solutions with high salt concentrations, autolysis of N358D is NaCl-dependent
W99R/I135T/K347E/F779L
-
mutant enzyme form does not autolyze and does not cleave filamin C
M18R
P51186
influence on meat tenderness estimated
additional information
P51186
DNA mutation 1538+225G>T and DNA mutation 2443-103G>C, influence on meat tenderness estimated
additional information
Q92177
DNA mutations 11818T>A and 12814T>G result in higher body weight and influence breast and leg muscle percentage and carcass weight
L212SfsX8
-
limb-girdle muscular dystrophy 2A
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
-
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
-
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
C129S
-
inactive
additional information
-
mutations result in limb girdle muscular dystrophy type 2A