Reviewed,
UniProtKB/Swiss-Prot P42574 (CASP3_HUMAN)
Last modified
November 25, 2008.
Version 110.
History...
Clusters with 100%,
90%,
50% identity |
Documents (8) |
Third-party data |
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Names and origin
| Protein names | Recommended name: Caspase-3 Short name=CASP-3 EC=3.4.22.56 Alternative name(s): Apopain Cysteine protease CPP32 Short name=CPP-32 Yama protein SREBP cleavage activity 1 Short name=SCA-1 Cleaved into the following 2 chains: 1- Recommended name: Caspase-3 subunit p17 2- Recommended name: Caspase-3 subunit p12 | ||||
| Gene names |
| ||||
| Organism | Homo sapiens (Human) | ||||
| Taxonomic identifier | 9606 [NCBI] | ||||
| Taxonomic lineage | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Protein attributes
| Sequence length | 277 AA. |
| Sequence status | Complete. |
| Sequence processing | The displayed sequence is further processed into a mature form. |
| Protein existence | Evidence at protein level. |
General annotation (Comments)
| Function | Involved in the activation cascade of caspases responsible for apoptosis execution. At the onset of apoptosis it proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly-217' bond. Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop-helix leucine zipper domain and the membrane attachment domain. Cleaves and activates caspase-6, -7 and -9. Involved in the cleavage of huntingtin. |
| 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. |
| Enzyme regulation | Inhibited by isatin sulfonamides. |
| Subunit structure | Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 17 kDa (p17) and a 12 kDa (p12) subunit. |
| Subcellular location | |
| 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. |
| Post-translational modification | Cleavage by granzyme B, caspase-6, caspase-8 and caspase-10 generates the two active subunits. Additional processing of the propeptides is likely due to the autocatalytic activity of the activated protease. Active heterodimers between the small subunit of caspase-7 protease and the large subunit of caspase-3 also occur and vice versa. 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. |
| Sequence similarities | Belongs to the peptidase C14 family. |
Ontologies
Keywords | |
|---|---|
| Biological process | Apoptosis |
| Cellular component | Cytoplasm |
| Coding sequence diversity | Polymorphism |
| Molecular function | Hydrolase Protease Thiol protease |
| PTM | Phosphoprotein S-nitrosylation Zymogen |
| Technical term | 3D-structure Direct protein sequencing |
Gene Ontology (GO) | |
| Uncategorized | caspase activity Inferred from Experiment. Source: Reactome |
| Biological process | negative regulation of apoptosis Inferred from genetic interaction. Source: MGI nuclear fragmentation during apoptosisInferred from mutant phenotype. Source: HGNC proteolysisInferred from direct assay. Source: UniProtKB |
| Cellular component | cytosol Inferred from direct assay. Source: UniProtKB mitochondrionInferred from direct assay. Source: HPA nucleoplasmInferred from Experiment. Source: Reactome plasma membraneInferred from Experiment. Source: Reactome |
| Molecular function | cysteine-type endopeptidase activity Traceable author statement. Source: ProtInc protein bindingInferred from physical interaction. Source: UniProtKB |
| Complete GO annotation... | |
Binary interactions
With | Entry | #Exp. | IntAct | Notes |
|---|---|---|---|---|
| BIRC2 | Q13490 | 1 | EBI-524064,EBI-514538 | |
| BIRC7 | Q96CA5 | 1 | EBI-524064,EBI-517623 | |
| WNK3 | Q9BYP7 | 2 | EBI-524064,EBI-1182602 |
Sequence annotation (Features)
| Feature key | Position(s) | Length | Description | Graphical view | Feature identifier | |||||||||||||||||||||||||||||||||||||||||||||||
Molecule processing | ||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Propeptide | 1 – 9 | 9 | PRO_0000004569 | |||||||||||||||||||||||||||||||||||||||||||||||||
| Propeptide | 10 – 28 | 19 | PRO_0000004570 | |||||||||||||||||||||||||||||||||||||||||||||||||
| Chain | 29 – 175 | 147 | Caspase-3 subunit p17 | PRO_0000004571 | ||||||||||||||||||||||||||||||||||||||||||||||||
| Chain | 176 – 277 | 102 | Caspase-3 subunit p12 | PRO_0000004572 | ||||||||||||||||||||||||||||||||||||||||||||||||
Sites | ||||||||||||||||||||||||||||||||||||||||||||||||||||
| Active site | 121 | 1 | By similarity | |||||||||||||||||||||||||||||||||||||||||||||||||
| Active site | 163 | 1 | By similarity | |||||||||||||||||||||||||||||||||||||||||||||||||
Amino acid modifications | ||||||||||||||||||||||||||||||||||||||||||||||||||||
| Modified residue | 26 | 1 | Phosphoserine By similarity | |||||||||||||||||||||||||||||||||||||||||||||||||
| Modified residue | 163 | 1 | S-nitrosocysteine; in inhibited form | |||||||||||||||||||||||||||||||||||||||||||||||||
Natural variations | ||||||||||||||||||||||||||||||||||||||||||||||||||||
| Natural variant | 190 | 1 | E → D | VAR_001401 | ||||||||||||||||||||||||||||||||||||||||||||||||
Experimental info | ||||||||||||||||||||||||||||||||||||||||||||||||||||
| Sequence conflict | 31 – 36 | 6 | ISLDNS → MSWDTG in CAC88866. Ref.3 | |||||||||||||||||||||||||||||||||||||||||||||||||
Secondary structure | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Helix Strand Turn | ||||||||||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 41 – 51 | 11 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Helix | 57 – 59 | 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Helix | 67 – 80 | 14 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 84 – 90 | 7 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Helix | 93 – 105 | 13 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 111 – 120 | 10 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 126 – 129 | 4 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 132 – 135 | 4 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Helix | 136 – 141 | 6 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Turn | 145 – 147 | 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Helix | 149 – 151 | 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 156 – 162 | 7 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 165 – 167 | 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Turn | 189 – 192 | 4 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 193 – 199 | 7 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 206 – 208 | 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Turn | 209 – 211 | 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Helix | 214 – 226 | 13 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Turn | 227 – 229 | 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Helix | 232 – 246 | 15 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Helix | 254 – 256 | 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 264 – 267 | 4 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 270 – 272 | 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 275 – 277 | 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||
Sequences
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References
| « Hide 'large scale' references | |
| [1] | "CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme." Fernandes-Alnemri T., Litwack G., Alnemri E.S. J. Biol. Chem. 269:30761-30764(1994) [PubMed: 7983002] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT ASP-190. Tissue: T-cell. |
| [2] | "Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase." Tewari M., Quan L.T., O'Rourke K., Desnoyers S., Zeng Z., Beidler D.R., Poirier G.G., Salvesen G.S., Dixit V.M. Cell 81:801-809(1995) [PubMed: 7774019] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. |
| [3] | "Caspase 3 activation is controlled by a sequence located in the N-terminus of its large subunit." Pelletier M., Cartron P.F., Delaval F., Meflah K., Vallette F.M., Oliver L. Biochem. Biophys. Res. Commun. 316:93-99(2004) [PubMed: 15003516] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT ASP-190. |
| [4] | "NIEHS-SNPs, environmental genome project, NIEHS ES15478, Department of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu)." Rieder M.J., Livingston R.J., Daniels M.R., Montoya M.A., Chung M.-W., Miyamoto K.E., Nguyen C.P., Nguyen D.A., Poel C.L., Robertson P.D., Schackwitz W.S., Sherwood J.K., Witrak L.A., Nickerson D.A. Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. |
| [5] | "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Lymph. |
| [6] | "Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis." Nicholson D.W., Ali A., Thornberry N.A., Vaillancourt J.P., Ding C.K., Gallant M., Gareau Y., Griffin P.R., Labelle M., Lazebnik Y.A., Munday N.A., Raju S.M., Smulson M.E., Yamin T.-T., Li V.L., Miller D.K. Nature 376:37-43(1995) [PubMed: 7596430] [Abstract] Cited for: PROTEIN SEQUENCE OF 29-46 AND 175-193, FUNCTION, VARIANT ASP-190. |
| [7] | "In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains." Fernandes-Alnemri T., Armstrong R.C., Krebs J.F., Srinivasula S.M., Wang L., Bullrich F., Fritz L.C., Trapani J.A., Tomaselli K.J., Litwack G., Alnemri E.S. Proc. Natl. Acad. Sci. U.S.A. 93:7464-7469(1996) [PubMed: 8755496] [Abstract] Cited for: PROTEOLYTIC PROCESSING. |
| [8] | "Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract." Goldberg Y.P., Nicholson D.W., Rasper D.M., Kalchman M.A., Koide H.B., Graham R.K., Bromm M., Kazemi-Esfarjani P., Thornberry N.A., Vaillancourt J.P., Hayden M.R. Nat. Genet. 13:442-449(1996) [PubMed: 8696339] [Abstract] Cited for: CLEAVAGE OF HUNTINGTIN. |
| [9] | "Fas-induced caspase denitrosylation." Mannick J.B., Hausladen A., Liu L., Hess D.T., Zeng M., Miao Q.X., Kane L.S., Gow A.J., Stamler J.S. Science 284:651-654(1999) [PubMed: 10213689] [Abstract] Cited for: S-NITROSYLATION. |
| [10] | "The three-dimensional structure of apopain/CPP32, a key mediator of apoptosis." Rotonda J., Nicholson D.W., Fazil K.M., Gallant M., Gareau Y., Labelle M., Peterson E.P., Rasper D.M., Ruel R., Vaillancourt J.P., Thornberry N.A., Becker J.W. Nat. Struct. Biol. 3:619-625(1996) [PubMed: 8673606] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 28-277. |
| [11] | "Structure of recombinant human CPP32 in complex with the tetrapeptide acetyl-Asp-Val-Ala-Asp fluoromethyl ketone." Mittl P.R.E., di Marco S., Krebs J.F., Bai X., Karanewsky D.S., Priestle J.P., Tomaselli K.J., Gruetter M.G. J. Biol. Chem. 272:6539-6547(1997) [PubMed: 9045680] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 35-173 AND 185-277. |
| [12] | "Potent and selective nonpeptide inhibitors of caspases 3 and 7 inhibit apoptosis and maintain cell functionality." Lee D., Long S.A., Adams J.L., Chan G., Vaidya K.S., Francis T.A., Kikly K., Winkler J.D., Sung C.-M., Debouck C., Richardson S., Levy M.A., DeWolf W.E. Jr., Keller P.M., Tomaszek T., Head M.S., Ryan M.D., Haltiwanger R.C. Nuttall M.E.J. Biol. Chem. 275:16007-16014(2000) [PubMed: 10821855] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS). |
| + | Additional computationally mapped references. |
Cross-references
Sequence databases | |
|---|---|
| U13737 mRNA. Translation: AAA65015.1. U13738 mRNA. Translation: AAB60355.1. U26943 mRNA. Translation: AAA74929.1. AJ413269 mRNA. Translation: CAC88866.1. AY219866 Genomic DNA. Translation: AAO25654.1. BC016926 mRNA. Translation: AAH16926.1. | |
| PIR | A55315. |
| RefSeq | NP_004337.2. NP_116786.1. |
| UniGene | Hs.141125 |
3D structure databases | |

Clusters with