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Information on EC 3.4.22.55 - caspase-2 and Organism(s) Homo sapiens and UniProt Accession P42575
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3.4.22.55 caspase-2Specify your search results
Word Map
- 3.4.22.55
-
caspases
- bcl-2
- necrosis
- bid
-
proapoptotic
-
anti-apoptotic
- parp
- raidd
-
apoptosis-inducing
-
caspase-dependent
- z-vad-fmk
-
p53-induced
-
tunel
-
jurkat
-
polyadp-ribose
-
casps
-
mitochondria-mediated
-
non-apoptotic
-
pan-caspase
- apaf-1
- apoptosome
-
caspase-mediated
-
death-inducing
- cpp32
- fasl
- z-devd-fmk
-
executioner
- xiap
-
damage-induced
-
etoposide-induced
-
anti-fas
- prodomains
-
p53-dependent
-
trail-induced
-
executor
-
bh3-only
- ac-devd-cho
-
apoptogenic
-
trail-mediated
-
procaspase
- caspase-10
- chk1
-
beta-converting
-
mitochondria-dependent
- medicine
- diagnostics
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
Reaction Schemes
strict requirement for an Asp residue at P1, with Asp316 being essential for proteolytic activity and has a preferred cleavage sequence of Val-Asp-Val-Ala-Asp-/-
Synonyms
caspase-2, caspase 2, casp2, ich-1, casp-2, caspase-2l, nedd-2, caspase-2s, ajcasp, ich-1 protease, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
caspase-2
-
caspase-2L
caspase-2S
C14.006
-
-
-
-
CASP-2
-
-
-
-
caspase 2
caspase-2
-
-
ICH-1 protease
-
-
-
-
ICH-1L/1S
-
-
-
-
caspase 2
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
strict requirement for an Asp residue at P1, with Asp316 being essential for proteolytic activity and has a preferred cleavage sequence of Val-Asp-Val-Ala-Asp-/-
catalysis is mediated by a mechanism involving a catalytic dyad composed of a cysteine residue as the catalytic nucleophile and a histidine residue
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
182372-14-1
-
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
Ac-DEVD-7-amino-4-trifluoromethyl coumarin + H2O
7-amino-4-trifluoromethyl coumarin + Ac-DEVD
37°C, pH 7.0, 10 mM dithiothreitol
-
-
?
Ac-VDVAD-7-amido-4-trifluoromethylcoumarin + H2O
Ac-VDVAD + 7-amido-4-trifluoromethylcoumarin
-
-
-
?
catalytically inactive pro-caspase-2 + H2O
caspase-2
37°C, pH 7.0, 10 mM dithiothreitol
-
-
?
eukaryotic translation initiation factor 4B + H2O
?
Asp563 in eukaryotic translation initiation factor 4B is a caspase-2-preferred cleavage site
-
-
?
N-acetyl-Val-Asp-Val-Ala-Asp-7-amido-4-methylcoumarin + H2O
N-acetyl-Val-Asp-Val-Ala-Asp + 7-amino-4-methylcoumarin
-
-
-
?
N-acetyl-VDVAD-7-amido-4-methylcoumarin + H2O
N-acetyl-VDVAD + 7-amino-4-methylcoumarin
-
-
-
?
procaspase-8 + H2O
processed procaspase-8
processing occurs between the large and small subunits
p43/41 form
-
?
Z-VDVAD-7-amino-4-trifluoromethyl coumarin + H2O
7-amino-4-trifluoromethyl coumarin + Z-VDVAD
37°C, pH 7.0, 10 mM dithiothreitol
-
-
?
acetyl-DEHD-7-amido-4-methylcoumarin + H2O
acetyl-DEHD + 7-amino-4-methylcoumarin
-
DEHD is the optimal tetrapeptide recognition motif
-
-
?
acetyl-Val-Asp-Val-Ala-Asp-4-nitroanilide + H2O
acetyl-Val-Asp-Val-Ala-Asp + 4-nitroaniline
-
-
-
-
?
Bid + H2O
tBid + ?
-
active caspase-2 cleaves Bid to form tBid, which induces mitochondrial outer membrane permeabilization
-
-
?
MDM2 + H2O
MDM2 p60 + ?
-
active caspase-2 cleaves MDM2 to form MDM2 p60, which binds to and stabilizes p53
-
-
?
NF kappaB activator + H2O
?
-
RIP1
proteolytic fragments of approximate 56 kDa and 20 kDa
-
?
Val-Asp-Val-Ala-Asp-7-amido-4-methylcoumarin + H2O
Val-Asp-Val-Ala-Asp + 7-amino-4-methylcoumarin
-
-
-
-
?
Val-Asp-Val-Ala-Asp-7-amido-4-trifluoromethylcoumarin + H2O
Val-Asp-Val-Ala-Asp + 7-amino-4-trifluoromethylcoumarin
-
-
-
-
?
Mdm2 protein + H2O
?
caspase-2 cleaves and inhibits Mdm2 and thereby promotes the stability of the tumor-suppressor p53
-
-
?
tau protein + H2O
?
caspase-2 cleavage of tau at Asp314 impairs cognitive and synaptic function in animal and cellular models of tauopathies by promoting the missorting of tau to dendritic spines. The truncation product, DELTAtau314, resists fibrillation and is present at higher levels in brains from cognitively impaired mice and humans with Alzheimer's disease
-
-
?
Mdm2 + H2O
processed Mdm2 + p60
-
Mdm2 contains a well-conserved caspase cleavage site, Asp-Val-Pro-Asp or DVPD, at which cleavage generates an 60 kDa N-terminal product. No activity with Mdm2 mutants D367A and D367E
-
-
?
procaspase-7 + H2O
caspase-7 + ?
-
activation by cleavage at Asp198 and Asp206
-
-
?
additional information
?
-
caspase-2 protein substrate recognition and catalysis, structural basis for the essential P5 recognition of caspase-2, molecular replacement and modeling using the structure with PDB ID 1PYO, overview. The key residues involved in catalysis, including the catalytic dyad, formed by Thr380 and Tyr420, and the invariant Arg378, superpose with each other regardless of the peptide inhibitor binding. Caspase-2 uniquely prefers a pentapeptide, such as VDVAD, rather than a tetrapeptide, as required for efficient cleavage by other caspases. The P3 Val is only involved in main chain hydrogen bonds with Arg378, and its side chain makes no contacts with the enzyme. The nitrogen atom of P4 Asp forms a hydrogen bond with the carbonyl oxygen of Tyr420, and its side chain extensively interacts with the enzyme through hydrogen bonds with the backbone of Tyr420 and the side chains of Trp385, Asn379, Arg417, and Glu418
-
-
?
additional information
?
-
-
caspase-2 protein substrate recognition and catalysis, structural basis for the essential P5 recognition of caspase-2, molecular replacement and modeling using the structure with PDB ID 1PYO, overview. The key residues involved in catalysis, including the catalytic dyad, formed by Thr380 and Tyr420, and the invariant Arg378, superpose with each other regardless of the peptide inhibitor binding. Caspase-2 uniquely prefers a pentapeptide, such as VDVAD, rather than a tetrapeptide, as required for efficient cleavage by other caspases. The P3 Val is only involved in main chain hydrogen bonds with Arg378, and its side chain makes no contacts with the enzyme. The nitrogen atom of P4 Asp forms a hydrogen bond with the carbonyl oxygen of Tyr420, and its side chain extensively interacts with the enzyme through hydrogen bonds with the backbone of Tyr420 and the side chains of Trp385, Asn379, Arg417, and Glu418
-
-
?
additional information
?
-
no activity with N-acetyl-Asp-Glu-Val-Asp-7-amido-4-methylcoumarin
-
-
?
additional information
?
-
-
no cleavage of acetyl-YVAD-4-nitroanilide, acetyl-DEVD-4-nitroanilide, acetyl-VEID-4-nitroanilide and acetyl-VQVD-4-nitroanilide
-
-
?
additional information
?
-
-
caspase-2 activation regulates PS-341-induced mitochondrial depolarization and apoptosis, suggesting that caspase-2 can serve as a link between lysosomal and mitochondrial permeabilization
-
-
?
additional information
?
-
-
caspase-2 initiates caspase cascade after trichostatin A treatment and involves the formation of the PIDDosome (a complex of caspase-2-CRADD/RAIDD-PIDD)
-
-
?
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
eukaryotic translation initiation factor 4B + H2O
?
Asp563 in eukaryotic translation initiation factor 4B is a caspase-2-preferred cleavage site
-
-
?
Mdm2 protein + H2O
?
caspase-2 cleaves and inhibits Mdm2 and thereby promotes the stability of the tumor-suppressor p53
-
-
?
tau protein + H2O
?
caspase-2 cleavage of tau at Asp314 impairs cognitive and synaptic function in animal and cellular models of tauopathies by promoting the missorting of tau to dendritic spines. The truncation product, DELTAtau314, resists fibrillation and is present at higher levels in brains from cognitively impaired mice and humans with Alzheimer's disease
-
-
?
Bid + H2O
tBid + ?
-
active caspase-2 cleaves Bid to form tBid, which induces mitochondrial outer membrane permeabilization
-
-
?
MDM2 + H2O
MDM2 p60 + ?
-
active caspase-2 cleaves MDM2 to form MDM2 p60, which binds to and stabilizes p53
-
-
?
Val-Asp-Val-Ala-Asp-7-amido-4-methylcoumarin + H2O
Val-Asp-Val-Ala-Asp + 7-amino-4-methylcoumarin
-
-
-
-
?
additional information
?
-
-
caspase-2 activation regulates PS-341-induced mitochondrial depolarization and apoptosis, suggesting that caspase-2 can serve as a link between lysosomal and mitochondrial permeabilization
-
-
?
additional information
?
-
-
caspase-2 initiates caspase cascade after trichostatin A treatment and involves the formation of the PIDDosome (a complex of caspase-2-CRADD/RAIDD-PIDD)
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
glucocorticoid modulatory element-binding protein 1
GMEB1, endogenous inhibitor of pro-caspase-2 activation
-
protein kinase CK2
phosphorylates procaspase-2 directly at serine-157. When protein kinase CK2 activity is low, procaspase-2 is dephosphorylated, dimerized, and activated in a PIDDosome-independent manner
-
additional information
caspase-2 is not subject to inhibition by members of the IAP family of apoptosis inhibitors
-
additional information
-
caspase-2 is not subject to inhibition by members of the IAP family of apoptosis inhibitors
-
additional information
siRNA directed at caspase-2, inhibits TRAIL-induced cell death
-
additional information
-
KM-values above 0.01 mM are obtained with acetyl-WEHD-aldehyde, acetyl-YVAD-aldehyde, acetyl-AEVD-aldehyde or cowpox serpin CrmA
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
silibinin
caspase-2 and caspase-8 can activate each other in response to silibinin
sterol regulatory element binding protein 2
increases caspase-2 gene expression
-
ATM/ATR
-
caspase-2 is activated by ATM/ATR independently of p53 when Chk1 activity is repressed
-
p53-induced protein with a death domain
-
PIDD, caspase-2 is activated by the p53 target gene product PIDD, i.e. LRDD or leucine-rich repeats and death domain containing, in a complex called the caspase-2-PIDDosome
-
RAIDD
-
in response to cellular stresses, processed PIDD-CC binds to RAIDD in the cytoplasm, which recruits and activates caspase-2, overview
-
additional information
etoposide, staurosporine, pacritaxel and cyclohexamide treatment promotes exon 9-inclusion, increasing the ratio of caspase-2S to caspase-2L
-
additional information
photodynamic treatment, incubation with zinc(II)-phthalocyanine (0.0005 mM and 0.001 mM)and irradiated with red light
-
additional information
when protein kinase CK2 activity is low, procaspase-2 is dephosphorylated, dimerized, and activated in a PIDDosome-independent manner
-
additional information
-
the enzyme is activated during apoptosis by a caspase-3 (CPP32)-like protease. When cells are induced to undergo apoptosis, endogenous caspase-2 is first cleaved into three fragments of 32000-33000 Da and 14000 Da, which are then further processed into 18000 Da and 12000 Da active subunits
-
additional information
-
the topoisomerase-II inhibitor etoposide induces processing of procaspase-2
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.025
Ac-VDVAD-7-amido-4-trifluoromethylcoumarin
pH 6.5, 22°C, wild-type enzyme
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.6
Ac-VDVAD-7-amido-4-trifluoromethylcoumarin
pH 6.5, 22°C, wild-type enzyme
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
KM-values above 0.01 mM are obtained with acetyl-WEHD-aldehyde, acetyl-YVAD-aldehyde, acetyl-AEVD-aldehyde and cowpox serpin CrmA
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
caspase-2 levels are significantly reduced in human lung adenocarcinoma with wild-type p53
-
expression of c-Myc and caspase-2 are crucial for cytochrome c release from mitochondria during cytotoxic stress. Caspase-2 is important for cytosolic Bax to integrate into the outer mitochondrial membrane
-
treatment of melanoma cells with terfenadine induced DNA damage and caspases 2 activation. A selective inhibitor of caspase-2 (benzyloxycarbonyl-VDVAD-fluoromethylketone) protects melanoma cells from terfenadine-induced apoptosis
-
histone deacetylase inhibition leads to decreased protein kinase casein kinase 2 activity, which is followed by caspase-2 activation and partial cleavage of caspase-8 that sensitizes the tumor cell to TRAIL-induced apoptosis
-
PS-341 (bortezomib) induces a dose-dependent apoptosis in association with reactive oxygen species generation and cleavage of caspase-2 to its 33- and 14-kDa fragments. PS-341-induced caspase-2 activation is attenuated by a selective pharmacological inhibitor of cathepsin B (R-3032). Caspase-2 regulates mitochondrial permeability
-
thrombin initiates EMP generation from the human microvascular endothelial cell line HMEC-1. Caspase-2 plays a role in release of endothelial microparticles by controlling the proteolytic activation of ROCK-II
-
caspase 2 activation is required for release of cytochrome c and cell death
additional information
isoform casp-2S is undetectable in the SKOV3, H-1299 and HCT-116 p53-deficient cells
-
histone deacetylase inhibition leads to decreased protein kinase casein kinase 2 activity, which is followed by caspase-2 activation and partial cleavage of caspase-8 that sensitizes the tumor cell to TRAIL-induced apoptosis
-
caspase-2 activation occurs upstream of mitochondria in resveratrol-treated cells. The activated caspase-2 triggers mitochondrial apoptotic events by inducing conformational changes in Bax/Bak with subsequent release of cytochrome c, apoptosis-inducing factor, and endonuclease G. Caspase-2 contributes toward the mitochondrial translocation of Bid
-
histone deacetylase inhibition leads to decreased protein kinase casein kinase 2 activity, which is followed by caspase-2 activation and partial cleavage of caspase-8 that sensitizes the tumor cell to TRAIL-induced apoptosis
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
the enzyme is associated with the cytoplasmic face of Golgi membranes
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
caspase-2 is the most evolutionarily conserved member in the human caspase family
malfunction
loss of caspase-2 leads to enhanced tumor proliferation and progression
metabolism
caspase-2 cleavage of tau at Asp314 impairs cognitive and synaptic function in animal and cellular models of tauopathies by promoting the missorting of tau to dendritic spines. The truncation product, DELTAtau314, resists fibrillation and is present at higher levels in brains from cognitively impaired mice and humans with Alzheimer's disease
physiological function
evolution
-
caspase-2 is an evolutionarily conserved caspase with features of both initiator and executioner caspases
malfunction
physiological function
additional information
physiological function
apoptosis induced by doxorubicin and 5-fluorouracil is caspase-2-dependent
physiological function
caspase-2 plays important roles in stress-induced apoptosis, cell cycle regulation, and tumor suppression
physiological function
the long isoform, casp-2L, promotes apoptosis, whereas the short isoform, casp-2S, inhibits apoptosis. Isoform casp-2S is responsible for inhibiting DNA damage-induced cytoplasmic fodrin cleavage independent of cellular p53 status, and prevents cisplatin-induced membrane blebbing thereby affecting cellular apoptosis
physiological function
caspase-2 functions as a tumor suppressor in Kras-driven lung cancer in vivo. Caspase-2 cleaves and inhibits Mdm2 and thereby promotes the stability of the tumor-suppressor p53
malfunction
-
decreased caspase-2 and RAIDD expression is observed in mantle cell lymphoma tumor samples. In addition, drug resistance in childhood forms of acute lymphoblastic leukemia is correlated with decreased levels of caspase-2. In contrast, increased levels of caspase-2 in acute myelogenous leukemia and adult ALL are associated with decreased patient survival. Possibly inactivation of caspase-2 in tumors occurs through disruption of the pathway through mutation or improper regulation of a protein that regulates caspase-2 activity
malfunction
-
depletion of caspase-2 prevents p21 expression and thereby reverts the gamma-IR-induced senescent phenotype of wild-type HCT116 colon carcinoma cells into apoptosis, knockdown of none of the caspase-2-interacting components RAIDD, RIP or DNA-PKcs is able to mimic these processes, but knockdown of caspase-2 specifically impairs DNA damage-induced p21 expression, and silencing of caspase-2 impairs exogenous expression of p21 constructs containing 3'-UTR sequences, whereas overexpression of a caspase-2 mutant increases p21 levels. Silencing of caspase-2 impairs exogenous expression of p21 constructs containing 3'-UTR sequences
physiological function
-
caspase 2 represses transcription of the survivin gene, a general regulator of cell division and cytoprotection in tumors. This pathway involves caspase 2 proteolytic cleavage of the nuclearfactor kappaB (NFkappaB) activator, RIP1. Loss of RIP1 abolishes transcription of NFkappaB target genes, including survivin, resulting in deregulated mitotic transitions, enhanced apoptosis and suppression of tumorigenicityin vivo. Caspase 2 functions as an endogenous inhibitor of NFkappaB-dependent cell survival.
physiological function
-
caspase-2 activation is commonly associated with induction of IFN-beta-induced apoptosis in IFN-beta-sensitive melanoma cells
physiological function
-
caspases-2 and -8 are involved in the presenilin1/gamma-secretase-dependent cleavage of amyloid precursor protein after the induction of apoptosis
physiological function
-
discussion of the role of caspase-2 and potential contribution of the enzyme to the pathology of human diseases
physiological function
-
The increased expression of PIDD (p53-induced protein with a death domain) induced by p53 forms a complex with RAIDD and caspase-2 (termed a PIDDosome), which activates the protease. The processed caspase-2 acts as a canonical caspase in the mitochondrial-mediated pathway triggering cytochrome c release. Once released to the cytoplasm, cytochrome c binds to APAF-1 to form a wheel-like complex, the apoptosome, resulting in the activation of caspase-9 and subsequent cleavage of downstream caspases including caspase-3.
physiological function
-
caspase-2 is commonly required for DNA damage-induced p21 expression. Caspase-2 regulates p21 expression at the translational level, independently of its enzymatic activity but also not requiring known caspase-2-activating platforms
physiological function
-
role of caspase-2 in apoptosis, and caspase-2 may act as a tumor suppressor, mechanisms through which caspase-2 signals, e.g. involving PIDD, also known as LRDD or leucine-rich repeat and death domain-containing protein, caspase-2 pathways to apoptosis and cell cycle arrest, detailed overview. PIDD activation and more importantly caspase-2 activation is not always synonymous with induction of apoptosis, a threshold of caspase-2 activation must be reached before caspase-2-dependent apoptosis is engaged. Cleavage of Mdm2 is not the sole way caspase-2 can induce growth arrest
physiological function
-
upon DNA damage, p53 induction of the Caspase-2-PIDDosome creates a positive feedback loop that inhibits Mdm2, a key negative regulator of p53, and reinforces p53 stability and activity, contributing to cell survival and drug resistance, mechanism of Mdm2 inhibition that impacts p53 dynamics upon genotoxic stress, overview
additional information
caspase-2 is synthesized as an inactive zymogen. The zymogen sequence includes a long prodomain containing a CARD followed by a large domain, a linker, and a small domain. Caspase-2 undergoes autocatalytic activation to remove the prodomain and linker region to generate a stable dimer consisting of the large subunit p19 and the small subunit p12. This p19/p12 dimer self-associates to form the active caspase-2
additional information
-
caspase-2 is synthesized as an inactive zymogen. The zymogen sequence includes a long prodomain containing a CARD followed by a large domain, a linker, and a small domain. Caspase-2 undergoes autocatalytic activation to remove the prodomain and linker region to generate a stable dimer consisting of the large subunit p19 and the small subunit p12. This p19/p12 dimer self-associates to form the active caspase-2
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). CASP2_HUMAN
452
0
50685
Swiss-Prot
Mitochondrion (Reliability: 5)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
monomer
oligomer
caspase-2 undergoes autocatalytic activation to remove the prodomain and linker region to generate a stable dimer consisting of the large subunit p19, residues 170-333, and the small subunit p12, residues 348-452. This p19/p12 dimer self-associates to form the active caspase-2
dimer
-
caspase-2 is activated by dimerization, initiator caspases are present in the cell as inactive monomers and their activation is promoted by dimerization. Dimerization results when initiator caspases are recruited to large molecular weight protein complexes that act as signaling platforms
additional information
-
recruitment of caspase-2 to a higher molecular weight protein complex in cell extracts
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
proteolytic modification
caspase-2 undergoes autocatalytic activation to remove the prodomain and linker region to generate a stable dimer consisting of the large subunit p19 and the small subunit p12. This p19/p12 dimer self-associates to form the active caspase-2, forming a dimer, a tetramer, or a dimer-of-dimers
proteolytic modification
additional information
-
DNA damage induced by gamma-radiation triggers the phosphorylation of nuclear caspase-2 at S122 site within the prodomain leading to its cleavage and activation
proteolytic modification
-
the enzyme is activated during apoptosis by a caspase-3 (CPP32)-like protease. When cells are induced to undergo apoptosis, endogenous caspase-2 is first cleaved into three fragments of 32000-33000 Da and 14000 Da, which are then further processed into 18000 Da and 12000 Da active subunits
proteolytic modification
-
the activation site of the caspase is DQQD-/- (P4,P3,P2,P1)
proteolytic modification
-
caspase-2 processing occurs in goniothalamin-treated Jurkat cells, cleavage to its active subunit (33 kDa) occurs as early as 3 h
proteolytic modification
-
pattern of caspase-2 processing differs between its autocatalytic and caspase-8-mediated cleavage
proteolytic modification
-
the topoisomerase-II inhibitor etoposide induces processing of procaspase-2
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
wild-type and mutant caspase-2 enzymes complexed with peptide aldehyde inhibitors, incubation of 3 mg/ml protein with 1-5 mM peptide aldehyde inhibitor in DMSO at room temperature for 2 h, hanging drop vapour diffusion method, mixing of 0.002 ml of protein complex solution with 0.002 ml of reservoir solution containing 0.1 M HEPES, pH 7.0, 15% PEG 3350, 3 mM DTT, X-ray diffraction structure determination and analysis at 1.5-2.4 A resolution, molecular replacement
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C303A
D152A
pro-caspase mutant, like the wild-type, this mutant is efficiently processed between the large and the small subunit, however, it is not further processed to seperate the prodomain from the large subunit
D316A
fusion of the linker to the large subunit, toxic when expressed in yeast
D316A/D330A
abolishes auto-processing and reduces enzymatic activity dramatically, 840fold decrease in activity
D330A
fusion of the linker to the small subunit, slightly greater deleterious effect on enzyme activity than fusion to the large subunit (D316A), toxic when expressed in yeast
S340A
-
phosphorylation site, expression of mutant S340A more than doubles the sensitivity of cells to nocodazole-induced mitotic death compared with wild-type protein
additional information
-
knockdown of caspase-2 and overexpression of a caspase-2 mutant
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant procaspase-2 from Escherichia coli strain BL21(DE3) by nickel affinity and ion exchange chromatography to over 95%
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression of wild-type and mutant enzymes in Escherichia coli strain Bl21 (DE3) pLysS
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
diagnostics
high level of inactive, non-processed caspase-2 together with caspase-3 is used as a predictor of survival and complete remission in adults with acute myeloblastic or lymphoblastic leukemias
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Garcia-Calvo, M.; Peterson, E.P.; Leiting, B.; Ruel, R.; Nicholson, D.W.; Thornberry, N.A.
Inhibition of human caspases by peptide-based and macromolecular inhibitors
J. Biol. Chem.
273
32608-32613
1998
Homo sapiens
Garcia-Calvo, M.; Peterson, E.P.; Rasper, D.M.; Vaillancourt, J.P.; Zamboni, R.; Nicholson, D.W.; Thornberry, N.A.
Purification and catalytic properties of human caspase family members
Cell Death Differ.
6
362-369
1999
Homo sapiens
Chang, H.Y.; Yang, X.
Proteases from cell suicide: functions and regulation of caspases
Microbiol. Mol. Biol. Rev.
64
821-846
2000
Homo sapiens, Mus musculus
Thornberry, N.A.; Rano, T.A.; Peterson, E.P.; et al.
A combinatorial approach defines specificities of members of the caspase family and granzyme B. Functional relationships established for key mediators of apoptosis
J. Biol. Chem.
272
17907-17911
1997
Homo sapiens
Talanian, R.V.; Quinlan, C.; Trautz, S.; Hackett, M.C.; Mankovich, J.A.; Banach, D.; Ghayur, T.; Brady, K.D.; Wong, W.W.
Substrate specificities of caspase family proteases
J. Biol. Chem.
272
9677-9682
1997
Homo sapiens
Wang, L.; Miura M.; Bergeron, L.; Zhu, H.; Yuan, J.
Ich-1, an Ice/ced-3-related gene, encodes both positive and negative regulators of programmed cell death
Cell
78
739-750
1994
Homo sapiens (P42575)
Xue, D.; Shaham, S.; Horvitz, H.R.
The Caenorhabditis elegans cell-death protein CED-3 is a cysteine protease with substrate specificities similar to those of the human CPP32 protease
Genes Dev.
10
1073-1083
1996
Homo sapiens (P42575)
Mancini, M.; Machamer, C.E.; Roy, S.; Nicholson, D.W.; Thornberry, N.A.; Casciola-Rosen, L.A.; Rosen, A.
Caspase-2 is localized at the Golgi complex and cleaves golgin-160 during apoptosis
J. Cell. Biol.
149
603-612
2000
Homo sapiens
Li, H.; Bergeron, L.; Cryns, V.; Pasternack, M.S.; Zhu, H.; Shi, L.; Greenberg, A.; Yuan, J.
Activation of caspase-2 in apoptosis
J. Biol. Chem.
272
21010-21017
1997
Homo sapiens
Zhivotovsky, B.; Orrenius, S.
Caspase-2 function in response to DNA damage
Biochem. Biophys. Res. Commun.
331
859-867
2005
Homo sapiens (P42575)
Tyagi, A.; Singh, R.P.; Agarwal, C.; Agarwal, R.
Silibinin activates p53-caspase-2 pathway and causes caspase-mediated cleavage of Cip1/p21 in apoptosis induction in bladder transitional-cell papilloma RT4 cells: evidence for a regulatory loop between p53 and caspase-2
Carcinogenesis
27
2269-2280
2006
Homo sapiens (P42575), Homo sapiens
Shin, S.; Lee, Y.; Kim, W.; Ko, H.; Choi, H.; Kim, K.
Caspase-2 primes cancer cells for TRAIL-mediated apoptosis by processing procaspase-8
EMBO J.
24
3532-3542
2005
Homo sapiens (P42575)
Cheung, H.H.; Lynn Kelly, N.; Liston, P.; Korneluk, R.G.
Involvement of caspase-2 and caspase-9 in endoplasmic reticulum stress-induced apoptosis: a role for the IAPs
Exp. Cell Res.
312
2347-2357
2006
Homo sapiens (P42575)
Ho, P.K.; Jabbour, A.M.; Ekert, P.G.; Hawkins, C.J.
Caspase-2 is resistant to inhibition by inhibitor of apoptosis proteins (IAPs) and can activate caspase-7
FEBS J.
272
1401-1414
2005
Homo sapiens (P42575), Homo sapiens
Cristobal, J.; Stockert, J.C.; Villanueva, A.; Rello-Varona, S.; Juarranz, A.; Canete, M.
Caspase-2: a possible trigger of apoptosis induced in A-549 tumor cells by ZnPc photodynamic treatment
Int. J. Oncol.
28
1057-1063
2006
Homo sapiens (P42575)
Wagner, K.W.; Engels, I.H.; Deveraux, Q.L.
Caspase-2 can function upstream of bid cleavage in the TRAIL apoptosis pathway
J. Biol. Chem.
279
35047-35052
2004
Homo sapiens (P42575)
Enoksson, M.; Robertson, J.D.; Gogvadze, V.; Bu, P.; Kropotov, A.; Zhivotovsky, B.; Orrenius, S.
Caspase-2 permeabilizes the outer mitochondrial membrane and disrupts the binding of cytochrome c to anionic phospholipids
J. Biol. Chem.
279
49575-49578
2004
Homo sapiens (P42575)
Iwanaga, N.; Kamachi, M.; Aratake, K.; Izumi, Y.; Ida, H.; Tanaka, F.; Tamai, M.; Arima, K.; Nakamura, H.; Origuchi, T.; Kawakami, A.; Eguchi, K.
Regulation of alternative splicing of caspase-2 through an intracellular signaling pathway in response to pro-apoptotic stimuli
J. Lab. Clin. Med.
145
105-110
2005
Homo sapiens (P42575)
Logette, E.; Le Jossic-Corcos, C.; Masson, D.; Solier, S.; Sequeira-Legrand, A.; Dugail, I.; Lemaire-Ewing, S.; Desoche, L.; Solary, E.; Corcos, L.
Caspase-2, a novel lipid sensor under the control of sterol regulatory element binding protein 2
Mol. Cell. Biol.
25
9621-9631
2005
Homo sapiens (P42575), Homo sapiens
Filomenko, R.; Prvotat, L.; Rb, C.; Cortier, M.; Jeannin, J.F.; Solary, E.; Bettaieb, A.
Caspase-10 involvement in cytotoxic drug-induced apoptosis of tumor cells
Oncogene
2006
1-11
2006
Homo sapiens (P42575)
-
VanOosten, R.L.; Earel, J.K.; Griffith, T.S.
Histone deacetylase inhibitors enhance Ad5-TRAIL killing of TRAIL-resistant prostate tumor cells through increased caspase-2 activity
Apoptosis
12
561-571
2007
Homo sapiens
Sapet, C.; Simoncini, S.; Loriod, B.; Puthier, D.; Sampol, J.; Nguyen, C.; Dignat-George, F.; Anfosso, F.
Thrombin-induced endothelial microparticle generation: identification of a novel pathway involving ROCK-II activation by caspase-2
Blood
108
1868-1876
2006
Homo sapiens
Taghiyev, A.F.; Guseva, N.V.; Glover, R.A.; Rokhlin, O.W.; Cohen, M.B.
TSA-induced cell death in prostate cancer cell lines is caspase-2 dependent and involves the PIDDosome
Cancer Biol. Ther.
5
1199-1205
2006
Homo sapiens
Jangi, S.M.; Diaz-Perez, J.L.; Ochoa-Lizarralde, B.; Martin-Ruiz, I.; Asumendi, A.; Perez-Yarza, G.; Gardeazabal, J.; Diaz-Ramon, J.L.; Boyano, M.D.
H1 histamine receptor antagonists induce genotoxic and caspase-2-dependent apoptosis in human melanoma cells
Carcinogenesis
27
1787-1796
2006
Homo sapiens
Yeung, B.H.; Huang, D.C.; Sinicrope, F.A.
PS-341 (bortezomib) induces lysosomal cathepsin B release and a caspase-2-dependent mitochondrial permeabilization and apoptosis in human pancreatic cancer cells
J. Biol. Chem.
281
11923-11932
2006
Homo sapiens
Mohan, J.; Gandhi, A.A.; Bhavya, B.C.; Rashmi, R.; Karunagaran, D.; Indu, R.; Santhoshkumar, T.R.
Caspase-2 triggers Bax-Bak-dependent and -independent cell death in colon cancer cells treated with resveratrol
J. Biol. Chem.
281
17599-17611
2006
Homo sapiens, Mus musculus
Cao, X.; Bennett, R.L.; May, W.S.
c-Myc and caspase-2 are involved in activating Bax during cytotoxic drug-induced apoptosis
J. Biol. Chem.
283
14490-14496
2008
Homo sapiens
Baptiste-Okoh, N.; Barsotti, A.M.; Prives, C.
A role for caspase 2 and PIDD in the process of p53-mediated apoptosis
Proc. Natl. Acad. Sci. USA
105
1937-1942
2008
Homo sapiens
Karki, P.; Dahal, G.R.; Shin, S.Y.; Lee, J.S.; Cho, B.; Park, I.S.
Efficient cleavage of Bid and procaspase-7 by caspase-2 at lower pH
Protein Pept. Lett.
15
1044-1049
2008
Homo sapiens
Chae, S.S.; Yoo, C.B.; Jo, C.; Yun, S.M.; Jo, S.A.; Koh, Y.H.
Caspases-2 and -8 are involved in the presenilin1/gamma-secretase-dependent cleavage of amyloid precursor protein after the induction of apoptosis
J. Neurosci. Res.
88
1926-1933
2010
Homo sapiens
Chan, K.M.; Rajab, N.F.; Siegel, D.; Din, L.B.; Ross, D.; Inayat-Hussain, S.H.
Goniothalamin induces coronary artery smooth muscle cells apoptosis: the p53-dependent caspase-2 activation pathway
Toxicol. Sci.
116
533-548
2010
Homo sapiens
Kitevska, T.; Spencer, D.M.; Hawkins, C.J.
Caspase-2: controversial killer or checkpoint controller?
Apoptosis
14
829-848
2009
Homo sapiens (P42575)
Lee, J.C.; Su, C.L.; Chen, L.L.; Won, S.J.
Formosanin C-induced apoptosis requires activation of caspase-2 and change of mitochondrial membrane potential
Cancer Sci.
100
503-513
2009
Homo sapiens
Krumschnabel, G.; Sohm, B.; Bock, F.; Manzl, C.; Villunger, A.
The enigma of caspase-2: The laymens view
Cell Death Differ.
16
195-207
2009
Homo sapiens, Mus musculus
Shi, M.; Vivian, C.J.; Lee, K.J.; Ge, C.; Morotomi-Yano, K.; Manzl, C.; Bock, F.; Sato, S.; Tomomori-Sato, C.; Zhu, R.; Haug, J.S.; Swanson, S.K.; Washburn, M.P.; Chen, D.J.; Chen, B.P.; Villunger, A.; Florens, L.; Du, C.
DNA-PKcs-PIDDosome: a nuclear caspase-2-activating complex with role in G2/M checkpoint maintenance
Cell
136
508-520
2009
Homo sapiens, Mus musculus
Andersen, J.L.; Johnson, C.E.; Freel, C.D.; Parrish, A.B.; Day, J.L.; Buchakjian, M.R.; Nutt, L.K.; Thompson, J.W.; Moseley, M.A.; Kornbluth, S.
Restraint of apoptosis during mitosis through interdomain phosphorylation of caspase-2
EMBO J.
28
3216-3227
2009
Homo sapiens, Xenopus laevis
Bouchier-Hayes, L.
The role of caspase-2 in stress-induced apoptosis
J. Cell. Mol. Med.
14
1212-1224
2010
Homo sapiens, Mus musculus
Kamiya, T.; Okabayashi, T.; Yokota, S.; Kan, Y.; Ogino, J.; Yamashita, T.; Fujii, N.; Jimbow, K.
Increased caspase-2 activity is associated with induction of apoptosis in IFN-beta sensitive melanoma cell lines
J. Interferon Cytokine Res.
30
349-357
2010
Homo sapiens
Bouchier-Hayes, L.; Oberst, A.; McStay, G.P.; Connell, S.; Tait, S.W.; Dillon, C.P.; Flanagan, J.M.; Beere, H.M.; Green, D.R.
Characterization of cytoplasmic caspase-2 activation by induced proximity
Mol. Cell
35
830-840
2009
Homo sapiens
Olsson, M.; Vakifahmetoglu, H.; Abruzzo, P.M.; Hoegstrand, K.; Grandien, A.; Zhivotovsky, B.
DISC-mediated activation of caspase-2 in DNA damage-induced apoptosis
Oncogene
28
1949-1959
2009
Homo sapiens
Guha, M.; Xia, F.; Raskett, C.M.; Altieri, D.C.
Caspase 2-mediated tumor suppression involves survivin gene silencing
Oncogene
29
1280-1292
2010
Homo sapiens
Inayat-Hussain, S.H.; Chan, K.M.; Rajab, N.F.; Din, L.B.; Chow, S.C.; Kizilors, A.; Farzaneh, F.; Williams, G.T.
Goniothalamin-induced oxidative stress, DNA damage and apoptosis via caspase-2 independent and Bcl-2 independent pathways in Jurkat T-cells
Toxicol. Lett.
193
108-114
2010
Homo sapiens
Sohn, D.; Budach, W.; Jaenicke, R.U.
Caspase-2 is required for DNA damage-induced expression of the CDK inhibitor p21(WAF1/CIP1)
Cell Death Differ.
18
1664-1674
2011
Homo sapiens
Bouchier-Hayes, L.; Green, D.R.
Caspase-2: the orphan caspase
Cell Death Differ.
19
51-57
2012
Homo sapiens, Mus musculus
Tang, Y.; Wells, J.A.; Arkin, M.R.
Structural and enzymatic insights into caspase-2 protein substrate recognition and catalysis
J. Biol. Chem.
286
34147-34154
2011
Homo sapiens (P42575), Homo sapiens
Oliver, T.G.; Meylan, E.; Chang, G.P.; Xue, W.; Burke, J.R.; Humpton, T.J.; Hubbard, D.; Bhutkar, A.; Jacks, T.
Caspase-2-mediated cleavage of Mdm2 creates a p53-induced positive feedback loop
Mol. Cell
43
57-71
2011
Homo sapiens
Vakifahmetoglu-Norberg, H.; Norberg, E.; Perdomo, A.B.; Olsson, M.; Ciccosanti, F.; Orrenius, S.; Fimia, G.M.; Piacentini, M.; Zhivotovsky, B.
Caspase-2 promotes cytoskeleton protein degradation during apoptotic cell death
Cell Death Dis.
4
e940
2013
Homo sapiens (P42575)
Wejda, M.; Impens, F.; Takahashi, N.; Van Damme, P.; Gevaert, K.; Vandenabeele, P.
Degradomics reveals that cleavage specificity profiles of caspase-2 and effector caspases are alike
J. Biol. Chem.
287
33983-33995
2012
Homo sapiens (P42575), Homo sapiens
Han, C.; Zhao, R.; Kroger, J.; Qu, M.; Wani, A.A.; Wang, Q.E.
Caspase-2 short isoform interacts with membrane-associated cytoskeleton proteins to inhibit apoptosis
PLoS ONE
8
e67033
2013
Homo sapiens (P42575)
Terry, M.; Arya, R.; Mukhopadhyay, A.; Berrett, K.; Clair, P.; Witt, B.; Salama, M.; Bhutkar, A.; Oliver, T.
Caspase-2 impacts lung tumorigenesis and chemotherapy response in vivo
Cell Death Differ.
22
719-730
2015
Homo sapiens (P42575), Homo sapiens
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