P42574 · CASP3_HUMAN
- ProteinCaspase-3
- GeneCASP3
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids277 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis (PubMed:18723680, PubMed:20566630, PubMed:23650375, PubMed:35338844, PubMed:35446120, PubMed:7596430).
Following cleavage and activation by initiator caspases (CASP8, CASP9 and/or CASP10), mediates execution of apoptosis by catalyzing cleavage of many proteins (PubMed:18723680, PubMed:20566630, PubMed:23650375, PubMed:7596430).
At the onset of apoptosis, it proteolytically cleaves poly(ADP-ribose) polymerase PARP1 at a '216-Asp-|-Gly-217' bond (PubMed:10497198, PubMed:16374543, PubMed:7596430, PubMed:7774019).
Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop-helix leucine zipper domain and the membrane attachment domain (By similarity).
Cleaves and activates caspase-6, -7 and -9 (CASP6, CASP7 and CASP9, respectively) (PubMed:7596430).
Cleaves and inactivates interleukin-18 (IL18) (PubMed:37993714, PubMed:9334240).
Involved in the cleavage of huntingtin (PubMed:8696339).
Triggers cell adhesion in sympathetic neurons through RET cleavage (PubMed:21357690).
Cleaves and inhibits serine/threonine-protein kinase AKT1 in response to oxidative stress (PubMed:23152800).
Acts as an inhibitor of type I interferon production during virus-induced apoptosis by mediating cleavage of antiviral proteins CGAS, IRF3 and MAVS, thereby preventing cytokine overproduction (PubMed:30878284).
Also involved in pyroptosis by mediating cleavage and activation of gasdermin-E (GSDME) (PubMed:35338844, PubMed:35446120).
Cleaves XRCC4 and phospholipid scramblase proteins XKR4, XKR8 and XKR9, leading to promote phosphatidylserine exposure on apoptotic cell surface (PubMed:23845944, PubMed:33725486).
Cleaves BIRC6 following inhibition of BIRC6-caspase binding by DIABLO/SMAC (PubMed:36758104, PubMed:36758106).
Following cleavage and activation by initiator caspases (CASP8, CASP9 and/or CASP10), mediates execution of apoptosis by catalyzing cleavage of many proteins (PubMed:18723680, PubMed:20566630, PubMed:23650375, PubMed:7596430).
At the onset of apoptosis, it proteolytically cleaves poly(ADP-ribose) polymerase PARP1 at a '216-Asp-|-Gly-217' bond (PubMed:10497198, PubMed:16374543, PubMed:7596430, PubMed:7774019).
Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop-helix leucine zipper domain and the membrane attachment domain (By similarity).
Cleaves and activates caspase-6, -7 and -9 (CASP6, CASP7 and CASP9, respectively) (PubMed:7596430).
Cleaves and inactivates interleukin-18 (IL18) (PubMed:37993714, PubMed:9334240).
Involved in the cleavage of huntingtin (PubMed:8696339).
Triggers cell adhesion in sympathetic neurons through RET cleavage (PubMed:21357690).
Cleaves and inhibits serine/threonine-protein kinase AKT1 in response to oxidative stress (PubMed:23152800).
Acts as an inhibitor of type I interferon production during virus-induced apoptosis by mediating cleavage of antiviral proteins CGAS, IRF3 and MAVS, thereby preventing cytokine overproduction (PubMed:30878284).
Also involved in pyroptosis by mediating cleavage and activation of gasdermin-E (GSDME) (PubMed:35338844, PubMed:35446120).
Cleaves XRCC4 and phospholipid scramblase proteins XKR4, XKR8 and XKR9, leading to promote phosphatidylserine exposure on apoptotic cell surface (PubMed:23845944, PubMed:33725486).
Cleaves BIRC6 following inhibition of BIRC6-caspase binding by DIABLO/SMAC (PubMed:36758104, PubMed:36758106).
Catalytic activity
- Strict requirement for an Asp residue at positions P1 and P4. It has a preferred cleavage sequence of Asp-Xaa-Xaa-Asp-|- with a hydrophobic amino-acid residue at P2 and a hydrophilic amino-acid residue at P3, although Val or Ala are also accepted at this position.
Activity regulation
Inhibited by isatin sulfonamides (PubMed:10821855).
Inhibited by BIRC6; following inhibition of BIRC6-caspase binding by DIABLO/SMAC, BIRC6 is subjected to caspase cleavage, leading to an increase in active caspases (PubMed:36758104, PubMed:36758106).
Inhibited by BIRC6; following inhibition of BIRC6-caspase binding by DIABLO/SMAC, BIRC6 is subjected to caspase cleavage, leading to an increase in active caspases (PubMed:36758104, PubMed:36758106).
Features
Showing features for active site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Active site | 121 | |||||
Sequence: H | ||||||
Active site | 163 | |||||
Sequence: C |
GO annotations
Keywords
- Molecular function
- Biological process
Enzyme and pathway databases
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameCaspase-3
- EC number
- Short namesCASP-3
- Alternative names
- Cleaved into 2 chains
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionP42574
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Disease & Variants
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 9 | In P3-D3A mutant; abolished cleavage and activation, leading to prevent thiol protease activity; when associated with A-28 and A-175. | ||||
Sequence: D → A | ||||||
Natural variant | VAR_048616 | 22 | in dbSNP:rs35578277 | |||
Sequence: H → R | ||||||
Mutagenesis | 28 | In P3-D3A mutant; abolished cleavage and activation, leading to prevent thiol protease activity; when associated with A-9 and A-175. | ||||
Sequence: D → A | ||||||
Mutagenesis | 175 | In P3-D3A mutant; abolished cleavage and activation, leading to prevent thiol protease activity; when associated with A-9 and A-28. | ||||
Sequence: D → A | ||||||
Natural variant | VAR_001401 | 190 | in dbSNP:rs1049210 | |||
Sequence: E → D | ||||||
Mutagenesis | 207 | Abolished ADP-riboxanation by C.violaceum CopC. | ||||
Sequence: R → A |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 277 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for modified residue, propeptide, modified residue (large scale data), chain.
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Modified residue | 1 | UniProt | N-acetylmethionine | ||||
Sequence: M | |||||||
Propeptide | PRO_0000004569 | 1-9 | UniProt | ||||
Sequence: MENTENSVD | |||||||
Propeptide | PRO_0000004570 | 10-28 | UniProt | ||||
Sequence: SKSIKNLEPKIIHGSESMD | |||||||
Modified residue | 11 | UniProt | N6-acetyllysine | ||||
Sequence: K | |||||||
Modified residue | 26 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 26 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 29 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Chain | PRO_0000004571 | 29-175 | UniProt | Caspase-3 subunit p17 | |||
Sequence: SGISLDNSYKMDYPEMGLCIIINNKNFHKSTGMTSRSGTDVDAANLRETFRNLKYEVRNKNDLTREEIVELMRDVSKEDHSKRSSFVCVLLSHGEEGIIFGTNGPVDLKKITNFFRGDRCRSLTGKPKLFIIQACRGTELDCGIETD | |||||||
Modified residue | 163 | UniProt | S-nitrosocysteine; in inhibited form | ||||
Sequence: C | |||||||
Chain | PRO_0000004572 | 176-277 | UniProt | Caspase-3 subunit p12 | |||
Sequence: SGVDDDMACHKIPVEADFLYAYSTAPGYYSWRNSKDGSWFIQSLCAMLKQYADKLEFMHILTRVNRKVATEFESFSFDATFHAKKQIPCIVSMLTKELYFYH | |||||||
Modified residue | 207 | UniProt | (Microbial infection) ADP-riboxanated arginine | ||||
Sequence: R |
Post-translational modification
Cleavage by granzyme B, caspase-6, caspase-8 and caspase-10 generates the two active subunits (PubMed:35338844, PubMed:35446120, PubMed:7596430, PubMed:8755496).
Additional processing of the propeptides is likely due to the autocatalytic activity of the activated protease (PubMed:7596430, PubMed:8755496).
Active heterodimers between the small subunit of caspase-7 protease and the large subunit of caspase-3 also occur and vice versa (PubMed:7596430, PubMed:8755496).
Additional processing of the propeptides is likely due to the autocatalytic activity of the activated protease (PubMed:7596430, PubMed:8755496).
Active heterodimers between the small subunit of caspase-7 protease and the large subunit of caspase-3 also occur and vice versa (PubMed:7596430, PubMed:8755496).
S-nitrosylated on its catalytic site cysteine in unstimulated human cell lines and denitrosylated upon activation of the Fas apoptotic pathway, associated with an increase in intracellular caspase activity. Fas therefore activates caspase-3 not only by inducing the cleavage of the caspase zymogen to its active subunits, but also by stimulating the denitrosylation of its active site thiol.
Ubiquitinated by BIRC6; this activity is inhibited by DIABLO/SMAC.
(Microbial infection) ADP-riboxanation by C.violaceum CopC blocks CASP3 processing, preventing CASP3 activation and ability to recognize and cleave substrates.
Keywords
- PTM
Proteomic databases
2D gel databases
PTM databases
Expression
Tissue specificity
Highly expressed in lung, spleen, heart, liver and kidney. Moderate levels in brain and skeletal muscle, and low in testis. Also found in many cell lines, highest expression in cells of the immune system.
Gene expression databases
Organism-specific databases
Interaction
Subunit
Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 17 kDa (p17) and a 12 kDa (p12) subunit. Interacts with BIRC6/bruce.
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | P42574 | AKAP8 O43823 | 5 | EBI-524064, EBI-1237481 | |
BINARY | P42574 | AKT3 Q9Y243 | 2 | EBI-524064, EBI-296115 | |
BINARY | P42574 | APP P05067 | 4 | EBI-524064, EBI-77613 | |
BINARY | P42574 | ATXN3 P54252 | 9 | EBI-524064, EBI-946046 | |
BINARY | P42574 | CASP6 P55212 | 2 | EBI-524064, EBI-718729 | |
BINARY | P42574 | CASP9 P55211 | 2 | EBI-524064, EBI-516799 | |
BINARY | P42574 | DCTN1 Q14203-5 | 3 | EBI-524064, EBI-25840379 | |
BINARY | P42574 | HTT P42858 | 9 | EBI-524064, EBI-466029 | |
BINARY | P42574 | MDM2 Q00987 | 2 | EBI-524064, EBI-389668 | |
BINARY | P42574 | NMT2 O60551 | 2 | EBI-524064, EBI-3920273 | |
BINARY | P42574 | PARP1 P09874 | 2 | EBI-524064, EBI-355676 | |
BINARY | P42574 | SOHLH1 Q5JUK2 | 3 | EBI-524064, EBI-12288855 | |
BINARY | P42574 | TXN P10599 | 6 | EBI-524064, EBI-594644 | |
BINARY | P42574 | WNK3 Q9BYP7 | 2 | EBI-524064, EBI-1182602 | |
BINARY | P42574 | XIAP P98170 | 6 | EBI-524064, EBI-517127 |
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Sequence
- Sequence statusComplete
- Sequence processingThe displayed sequence is further processed into a mature form.
- Length277
- Mass (Da)31,608
- Last updated2005-10-11 v2
- Checksum2F35CD3BCF7FF64A
Computationally mapped potential isoform sequences
There are 3 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A8MVM1 | A8MVM1_HUMAN | CASP3 | 182 | ||
C9JXR7 | C9JXR7_HUMAN | CASP3 | 117 | ||
A0A8V8TPU5 | A0A8V8TPU5_HUMAN | CASP3 | 41 |
Features
Showing features for sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 31-36 | in Ref. 3; CAC88866 | ||||
Sequence: ISLDNS → MSWDTG |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
U13737 EMBL· GenBank· DDBJ | AAA65015.1 EMBL· GenBank· DDBJ | mRNA | ||
U13738 EMBL· GenBank· DDBJ | AAB60355.1 EMBL· GenBank· DDBJ | mRNA | ||
U26943 EMBL· GenBank· DDBJ | AAA74929.1 EMBL· GenBank· DDBJ | mRNA | ||
AJ413269 EMBL· GenBank· DDBJ | CAC88866.1 EMBL· GenBank· DDBJ | mRNA | ||
AK291337 EMBL· GenBank· DDBJ | BAF84026.1 EMBL· GenBank· DDBJ | mRNA | ||
AY219866 EMBL· GenBank· DDBJ | AAO25654.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471056 EMBL· GenBank· DDBJ | EAX04673.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471056 EMBL· GenBank· DDBJ | EAX04674.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471056 EMBL· GenBank· DDBJ | EAX04675.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC016926 EMBL· GenBank· DDBJ | AAH16926.1 EMBL· GenBank· DDBJ | mRNA |