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Literature summary for 3.4.22.55 extracted from

  • Tang, Y.; Wells, J.A.; Arkin, M.R.
    Structural and enzymatic insights into caspase-2 protein substrate recognition and catalysis (2011), J. Biol. Chem., 286, 34147-34154.
    View publication on PubMedView publication on EuropePMC

Cloned(Commentary)

Cloned (Comment) Organism
expression of wild-type and mutant enzymes in Escherichia coli strain Bl21 (DE3) pLysS Homo sapiens

Crystallization (Commentary)

Crystallization (Comment) Organism
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 Homo sapiens

Protein Variants

Protein Variants Comment Organism
T380A site-directed mutagenesis Homo sapiens
T380A/Y420A site-directed mutagenesis Homo sapiens
Y420A site-directed mutagenesis Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
Ac-ADVAD-CHO binding structure Homo sapiens
Ac-DVAD-CHO binding structure Homo sapiens
Ac-VDVAD-CHO binding structure Homo sapiens

KM Value [mM]

KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
0.025
-
Ac-VDVAD-7-amido-4-trifluoromethylcoumarin pH 6.5, 22°C, wild-type enzyme Homo sapiens

Organism

Organism UniProt Comment Textmining
Homo sapiens P42575
-
-

Posttranslational Modification

Posttranslational Modification Comment Organism
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 Homo sapiens

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
Ac-VDVAD-7-amido-4-trifluoromethylcoumarin + H2O
-
Homo sapiens Ac-VDVAD + 7-amido-4-trifluoromethylcoumarin
-
?
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 Homo sapiens ?
-
?

Subunits

Subunits Comment Organism
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 Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
22
-
assay at room temperature Homo sapiens

Turnover Number [1/s]

Turnover Number Minimum [1/s] Turnover Number Maximum [1/s] Substrate Comment Organism Structure
0.6
-
Ac-VDVAD-7-amido-4-trifluoromethylcoumarin pH 6.5, 22°C, wild-type enzyme Homo sapiens

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
6.5
-
assay at Homo sapiens

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.000025
-
pH 6.5, 22°C, wild-type enzyme Homo sapiens Ac-VDVAD-CHO
0.00011
-
pH 6.5, 22°C, wild-type enzyme Homo sapiens Ac-ADVAD-CHO
0.00071
-
pH 6.5, 22°C, wild-type enzyme Homo sapiens Ac-DVAD-CHO

General Information

General Information Comment Organism
evolution caspase-2 is the most evolutionarily conserved member in the human caspase family Homo sapiens
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 Homo sapiens
physiological function caspase-2 plays important roles in stress-induced apoptosis, cell cycle regulation, and tumor suppression Homo sapiens