Information on EC 3.4.22.57 - caspase-4

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The expected taxonomic range for this enzyme is: Euarchontoglires

EC NUMBER
COMMENTARY
3.4.22.57
-
RECOMMENDED NAME
GeneOntology No.
caspase-4
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
strict requirement for Asp at the P1 position. It has a preferred cleavage sequence of Tyr-Val-Ala-Asp-/- but also cleaves at Asp-Glu-Val-Asp-/-
show the reaction diagram
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
-
-
SYNONYMS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C14.007
-
-
-
-
Cas4
-
-
CASP-4
-
-
-
-
caspase 4
-
-
-
-
caspase-4
-
-
caspase-4
-
cf 3.4.22.64
ICE(rel)-II
-
-
-
-
ICH-2 protease
-
-
-
-
ICH-3 protease
-
-
-
-
ICH3 protease
-
-
-
-
TX
-
-
-
-
TX protease
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
182762-08-9
-
216503-96-7
-
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
TRAF6-caspase-4 interaction, triggered by LPS, leads to NFkappaB-dependent transcriptional up-regulation and secretion of important cytokines and chemokines in innate immune signaling in human monocytic cells
SwissProt
Manually annotated by BRENDA team
-
SwissProt
Manually annotated by BRENDA team
C57BL, wild type and p53KO mice
-
-
Manually annotated by BRENDA team
strain C57BL/6 X CBA
SwissProt
Manually annotated by BRENDA team
Mus musculus C57BL/6 X CBA
strain C57BL/6 X CBA
SwissProt
Manually annotated by BRENDA team
no activity in Mus musculus
-
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
-
caspase-4 is a member of the caspase family
evolution
-
caspase-4 is a member of the caspase-1 family
evolution
-
caspase-4 is a member of the caspase family and a member of the interleukin-1beta coverting enzyme subfamily
malfunction
-
overexpression of wild-type caspase-4 results in cytotoxicity, reflected by slightly enhanced amounts of beta-actin in the supernatant
physiological function
-
caspase-4 is involved in endoplasmic reticulum stress-induced apoptosis and is required for activation of inflammasomes. Caspase-4 expression is required for UVB-induced activation of proIL-1beta and for unconventional protein secretion by skin-derived keratinocytes, requiring expression of the nucleotide-binding domain leucine-rich repeat containing, Pyrin domain containing-3 inflammasome. Caspase-4 supports activation of caspase-1 and proIL-1beta processing in COS-1 cells
physiological function
-
caspase-4 directly activates caspase-9 in endoplasmic reticulum stress-induced apoptosis in SH-SY5Y cells, interaction between caspase-4 and caspase-9 in endoplasmic reticulum stress-induced apoptosis, overview
physiological function
-
caspase-4 is a member of the inflammatory family of caspases involved in the regulation of the endoplasmic reticulum stress response, autophagy and cell survival. Cell death is occurring through a caspase-independent mechanism
physiological function
-
acute inflammatory cell death in the intestinal tract is mediated by caspase-4
physiological function
-
caspase-4 is required for maturation of pro-interleukin-1beta through activation of caspase-1 in keratinocytes
physiological function
-
caspase-4 is involved in endotoxin sensitivity. Caspase-4 can support activation of caspase-1 and secretion of interleukin-1beta and interleukin-18 in response to priming signals (LPS or Pam3CSK4) alone, without the need for second signals to stimulate the assembly of the inflammasome
physiological function
-
caspase-4 activity is required for Fas-induced cell apoptosis
malfunction
-
when caspase-4 activity is blocked by the dominant negative form of nuclear factor-kappaB, Fas-induced cell death is substantially reduced
additional information
-
elevated caspase activity in Pt1 cells is an outcome of increased caspase-4 activation
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
Ac-Leu-Glu-Val-Asp-7-amido-4-trifluoro methylcoumarin + H2O
7-amino-4-trifluoromethylcoumarin + Ac-Leu-Glu-Val-Asp
show the reaction diagram
-
10 microM, 2 h, 37C, reaction stopped with HCl
-
?
acetyl-DEVD-4-nitroanilide + H2O
acetyl-DEVD + 4-nitroaniline
show the reaction diagram
-
-
-
?
acetyl-DQMD-4-nitroanilide + H2O
acetyl-DQMD + 4-nitroaniline
show the reaction diagram
-
-
-
?
acetyl-LEVDGW-amide + H2O
?
show the reaction diagram
-
preferred peptide substrate
-
-
?
acetyl-VEID-4-nitroanilide + H2O
acetyl-VEID + 4-nitroaniline
show the reaction diagram
-
-
-
?
acetyl-VQVD-4-nitroanilide + H2O
acetyl-VQVD + 4-nitroaniline
show the reaction diagram
-
-
-
?
acetyl-WEHD-7-amido-4-methylcoumarin + H2O
acetyl-WEHD + 7-amino-4-methylcoumarin
show the reaction diagram
-
WEHD is the optimal tetrapeptide recognition motif
-
?
acetyl-YEVD-4-nitroanilide + H2O
acetyl-YEVD + 4-nitroaniline
show the reaction diagram
-
-
-
?
acetyl-YVAD-4-nitroanilide + H2O
acetyl-YVAD + 4-nitroaniline
show the reaction diagram
-
-
-
?
acetyl-YVAD-amido-4-methylcoumarin + H2O
acetyl-YVAD + amino-4-methylcoumarin
show the reaction diagram
-
-
-
?
cowpox serpin CrmA + H2O
?
show the reaction diagram
-
-
-
-
?
p35 + H2O
?
show the reaction diagram
-
-
-
-
?
poly(ADP-ribose)polymerase + H2O
?
show the reaction diagram
-
-
-
-
?
procaspase-1 + H2O
caspase-1 + ?
show the reaction diagram
-
-
-
?
procaspase-1 + H2O
caspase-1 + ?
show the reaction diagram
-
-
-
?
procaspase-1 + H2O
caspase-1 + ?
show the reaction diagram
-
-
-
?
procaspase-1 + H2O
caspase-1 + ?
show the reaction diagram
-
caspase-4 processes caspase-1 and enhances secretion of IL-1beta in transfected COS-1 cells
-
?
procaspase-9 + H2O
caspase-9 + ?
show the reaction diagram
-
human recombinant active caspase-4 cleaves wild-type and D330A mutant caspase-9 at residue D315, but not the D315A mutant
-
?
succinyl-YVAD-4-nitroanilide + H2O
succinyl-YVAD + 4-nitroaniline
show the reaction diagram
-
-
-
?
succinyl-YVAD-4-nitroanilide + H2O
succinyl-YVAD + 4-nitroaniline
show the reaction diagram
-
-
-
?
succinyl-YVAD-4-nitroanilide + H2O
succinyl-YVAD + 4-nitroaniline
show the reaction diagram
-
-
-
?
succinyl-YVAD-amido-4-methylcoumarin + H2O
succinyl-YVAD + amino-4-methylcoumarin
show the reaction diagram
-
-
-
?
LEVD-7-amido-4-trifluoromethylcoumarin + H2O
LEVD + 7-amino-4-trifluoromethylcoumarin
show the reaction diagram
-
-
-
?
additional information
?
-
-
the enzyme cleaves the substrates in the order of increasing efficiency: p35, pro-caspase-3, CrmA
-
-
-
additional information
?
-
-
the preferred cleavage sequence is WEHD-/- or LEHD-/-
-
-
-
additional information
?
-
-
the enzyme is involved in cytokine activation
-
-
-
additional information
?
-
-
the production of the enzyme induces activation of CPP32 like casoase
-
-
-
additional information
?
-
-
overexpression of ICH-2 in insect cell induces apoptosis
-
-
-
additional information
?
-
the enzyme is capable of inducing apoptosis in transfected cells such as fibroblasts and may play a role in apoptotic cell death
-
-
-
additional information
?
-
-
overexpression of the enzyme induces apoptosis
-
-
-
additional information
?
-
-
caspase-4 can function as an ER-stress-specific caspase in humans, and may be involved in pathogenesis of Alzheimer's disease
-
-
-
additional information
?
-
-
protective role of CARD only protein in Rip2/caspase-1/caspase-4-mediated HeLa cell death. CARD only protein binds and inhibits caspase-4 activation
-
-
-
additional information
?
-
-
familial Alzheimer's disease-linked presenilin-1 mutation accelerates the cleavage of caspase-4 under the endoplasmic reticulum stress and results in the activation of caspase-9 and caspase-3, apoptosis signal, without releasing cytochrome-c
-
-
-
additional information
?
-
-
misfolded BRICHOS SP-C mutant proteins induce apoptosis via caspase-4- and cytochrome c-related mechanisms
-
-
-
additional information
?
-
-
caspase-4 physically interacts with its central molecule caspase-1
-
-
-
pro-caspase-3 + H2O
p12 + pro-p17
show the reaction diagram
-
-
-
?
pro-interleukin-1beta + H2O
additional information
-
-
-
-
?
pro-interleukin-1beta + H2O
additional information
-
-
-
generation of a small amount of mature interleukin-1beta after 120 min
?
pro-interleukin-1beta + H2O
additional information
-
-
less efficient cleavage than with EC 3.4.22.36, caspase-1. The enzyme cleaves between YVHD116 and A117 to generate the 17500 Da mature active interleukin-1beta. An additional cleavage site between FEAD27 and G28 generates a 28000 Da intermediate form
-
?
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
procaspase-1 + H2O
caspase-1 + ?
show the reaction diagram
-
-
-
?
procaspase-1 + H2O
caspase-1 + ?
show the reaction diagram
-
-
-
?
procaspase-1 + H2O
caspase-1 + ?
show the reaction diagram
-
caspase-4 processes caspase-1 and enhances secretion of IL-1beta in transfected COS-1 cells
-
?
procaspase-9 + H2O
caspase-9 + ?
show the reaction diagram
-
-
-
?
LEVD-7-amido-4-trifluoromethylcoumarin + H2O
LEVD + 7-amino-4-trifluoromethylcoumarin
show the reaction diagram
-
-
-
?
additional information
?
-
-
the enzyme is involved in cytokine activation
-
-
-
additional information
?
-
-
the production of the enzyme induces activation of CPP32 like casoase
-
-
-
additional information
?
-
-
overexpression of ICH-2 in insect cell induces apoptosis
-
-
-
additional information
?
-
P49662
the enzyme is capable of inducing apoptosis in transfected cells such as fibroblasts and may play a role in apoptotic cell death
-
-
-
additional information
?
-
-
overexpression of the enzyme induces apoptosis
-
-
-
additional information
?
-
-
caspase-4 can function as an ER-stress-specific caspase in humans, and may be involved in pathogenesis of Alzheimer's disease
-
-
-
additional information
?
-
-
protective role of CARD only protein in Rip2/caspase-1/caspase-4-mediated HeLa cell death. CARD only protein binds and inhibits caspase-4 activation
-
-
-
additional information
?
-
-
familial Alzheimer's disease-linked presenilin-1 mutation accelerates the cleavage of caspase-4 under the endoplasmic reticulum stress and results in the activation of caspase-9 and caspase-3, apoptosis signal, without releasing cytochrome-c
-
-
-
additional information
?
-
-
misfolded BRICHOS SP-C mutant proteins induce apoptosis via caspase-4- and cytochrome c-related mechanisms
-
-
-
additional information
?
-
-
caspase-4 physically interacts with its central molecule caspase-1
-
-
-
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
acetyl-AEVD-aldehyde
-
-
acetyl-DEVD-aldehyde
-
-
acetyl-IETD-aldehyde
-
-
acetyl-WEHD-aldehyde
-
-
acetyl-YVAD-aldehyde
-
-
acetyl-YVD-aldehyde
-
IC50: 748 nM
benzyloxycarbonyl-VAD-fluoromethylketone
-
-
cowpox serpin CrmA
-
inhibits cleavage of pro-caspase-3
-
cowpox serpin CrmA
-
-
-
iodoacetamide
-
-
iodoacetic acid
-
-
N-acetyl-LEVD-CHO
-
-
-
N-tert-butyloxycarbonyl-AEVD-aldehyde
-
-
N-tert-butyloxycarbonyl-IETD-aldehyde
-
-
OspC3
-
the effector molecule of Shigella flexneri interacts with the caspase-4-p19 subunit and inhibits its activation by preventing caspase-4-p19 and caspase-4-p10 heterodimerization by depositing the conserved OspC3 X1-Y-X2-D-X3 motif at the putative catalytic pocket of caspase-4
-
Z-LEVD-fluoromethylketone
-
caspase-4, -5, and -1 inhibitor
-
LEVD-CHO
-
a caspase-4 inhibitor, suppresses both the apoptosis and caspase-9 activation
-
additional information
-
not inhibited by the caspase-1-specific inhibitor acetyl-YVAD-aldehyde
-
additional information
-
no inhibition by E64
-
additional information
-
downregulation of caspase-4 expression in cells expressiong FE65 and Teashirt3
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
hepatocyte growth factor
-
-
-
interleukin 6
-
-
tunicamycin
-
activates caspase-4. Activation of caspase-4 preceeds that of caspase-9
Leukemia inhibitory factor
-
-
-
additional information
-
benzene, increase of caspase-4 expression after 12 days of oral benzene treatment to p53KO mice
-
additional information
-
increase of caspase-4 expression by reduced expression of Teashirt3
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.032
acetyl-DEVD-4-nitroanilide
-
pH 7.5, 30C
0.35
acetyl-DQMD-4-nitroanilide
-
pH 7.5, 30C
0.044
acetyl-LEVD-4-nitroanilide
-
pH 7.5, 30C
0.43
acetyl-LEVDGW-amide
-
pH 7.5, 30C
0.681
acetyl-Tyr-Val-Ala-Asp-4-nitroanilide
-
pH 7.0, 30C
0.205
acetyl-VEID-4-nitroanilide
-
pH 7.5, 30C
0.72
acetyl-VQVD-4-nitroanilide
-
pH 7.5, 30C
0.031
acetyl-WEHD-7-amido-4-methylcoumarin
-
pH 7.0
0.079
acetyl-WEHD-7-amido-4-methylcoumarin
-
pH 7.5
0.031
acetyl-YEVD-4-nitroanilide
-
pH 7.5, 30C
0.874
acetyl-YVAD-4-nitroanilide
-
pH 7.5, 30C
0.035
acetyl-YVAD-amido-4-methylcoumarin
-
pH 7.5
0.048
succinyl-YVAD-4-nitroanilide
-
pH 7.5
0.09
succinyl-YVAD-4-nitroanilide
-
pH 7.5, 37C
0.09
succinyl-YVAD-7-amido-4-methylcoumarin
-
pH 7.5, 37C
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1.2
acetyl-WEHD-7-amino-4-methylcoumarin
Homo sapiens
-
at pH 7.0 and pH 7.5
1.07
succinyl-YVAD-4-nitroanilide
Homo sapiens
-
pH 7.5, 37C
1.1
succinyl-YVAD-4-nitroanilide
Homo sapiens
-
pH 7.5
0.4
succinyl-YVAD-amido-4-methylcoumarin
Homo sapiens
-
pH 7.5, 37C
0.5
acetyl-YVAD-amido-4-methylcoumarin
Homo sapiens
-
pH 7.5
additional information
additional information
Homo sapiens
-
-
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000375
acetyl-AEVD-aldehyde
-
pH 7.5, 25C
0.000132
acetyl-DEVD-aldehyde
-
pH 7.5, 25C
0.00015
acetyl-DEVD-aldehyde
-
pH 7.5, 37C
0.0004
acetyl-IETD-aldehyde
-
pH 7.5, 25C
0.000097
acetyl-WEHD-aldehyde
-
pH 7.5, 25C
0.00002
acetyl-YVAD-aldehyde
-
pH 7.5, 37C
0.000362
acetyl-YVAD-aldehyde
-
pH 7.5, 25C
0.0000011
cowpox serpin CrmA
-
pH 7.5, 25C
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000748
acetyl-YVD-aldehyde
Homo sapiens
-
IC50: 748 nM
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7
-
reaction with acetyl-WEHD-7-amido-4-methylcoumarin
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
-
2 h incubation time
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
primary, activated
Manually annotated by BRENDA team
-
caspase-4 is upregulated in lymphoblastoid cells
Manually annotated by BRENDA team
-
neuroblastoma cell
Manually annotated by BRENDA team
additional information
no activity detected in brain
Manually annotated by BRENDA team
additional information
-
no activity detected in brain
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
?
-
x * 35000, active enzyme, SDS-PAGE
additional information
-
expression in baculovirus-infected insect cells as 30000 Da proteins lacking the propeptide. Automaturation into p20 and p10 subunits occurs within the cells
additional information
-
purified N-His IVH-2 migrates on an SDS-PAGE as two bands with approximately molecular masses of 20000 Da and 10000 Da
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
proteolytic modification
-
the activation site of caspase is WVRD-/-
proteolytic modification
-
synthesized as larger proenzyme which is proteolytically processed to form heterodimeric active enzyme
proteolytic modification
-
expression in baculovirus-infected insect cells as 30000 Da proteins lacking the propeptide. Automaturation into p20 and p10 subunits occurs within the cells
proteolytic modification
-
cleavage of pro-caspase-4 when cells are treated with stress-inducing reagents
proteolytic modification
-
tunicamycin and thapsigargin induce caspase-4 mRNA expression and protein activation, cleavage of caspase-4 is not affected by overexpression of Bcl-2
proteolytic modification
-
procaspase-4 is activated to mature caspase-4
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
recombinant His6-tagged enzyme
-
recombinant T7-tagged enzyme
-
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli BL21(DE3) cells
-
expressed in Mus musculus
-
expression in baculovirus-infected insect cells as 30000 Da proteins lacking the propeptide. Automaturation into p20 and p10 subunits occurs within the cells
-
expression in Escherichia coli
-
expression in Escherichia coli; full-length clones are originally transfected into various host cells, including COS-M6, RAT-1 and HeLa
-
expression of wild-type, native caspase-4, of C-terminal Myc-tagged wild-type vcaspase-4, and of caspase-4 mutant C285A in COS-1 cells, co-expression with caspase-1
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
c-Rel is a negative regulator of caspase-4, e.g. in EBV lymphoblastoid cells
-
the dominant negative form of IkappaBalpha suppresses the expression of caspase-4
-
c-Rel as well as other endoplasmic reticulum stress genes directly modulate expression of caspase-4
-
caspase-4 protein expression is strongly induced in the lesional stratum corneum of patients suffering from psoriasis, a common chronic inflammatory disease
-
tunicamycin and thapsigargin induce caspase-4 mRNA expression and protein activation
-
apoptosis-independent cell death is accompanied by increased expression of the inflammatory marker, caspase-4. Caspase-4 is upregulated in Pt1 cells and induced by interferons
-
mRNA expression of the pro-form of caspase-4 is up-regulated 2fold after poly-I:C stimulation
-
enhancement of nuclear factor-kappaB activity by p65 (RelA) overexpression increases the expression of caspase-4 at both mRNA and protein levels
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
knockdown expression of caspase-4 with siRNA in keratinocytes, overexpression of active caspase-4 rescues UVB-induced secretion of IL-1b by caspase-4 knockdown keratinocytes
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
-
caspase-4 represents a target for the treatment of (auto)inflammatory diseases
medicine
-
regulation of the expression, activation, or activity of caspase-4 represents targets for systemic inflammatory response syndrome, sepsis, septic shock, and related disorders