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Reviewed, UniProtKB/Swiss-Prot P42574 (CASP3_HUMAN)

Last modified June 16, 2009. Version 118. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

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Names and origin

Protein namesRecommended 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
Name: CASP3
Synonyms: CPP32
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length277 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level.

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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. Ref.6

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

Cytoplasm.

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 C14A family.

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Binary interactions

With

Entry

#Exp.

IntAct

Notes

BIRC2Q134901EBI-524064,EBI-514538
BIRC7Q96CA51EBI-524064,EBI-517623
WNK3Q9BYP72EBI-524064,EBI-1182602

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Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Propeptide1 – 99
PRO_0000004569
Propeptide10 – 2819 Ref.6
PRO_0000004570
Chain29 – 175147Caspase-3 subunit p17
PRO_0000004571
Chain176 – 277102Caspase-3 subunit p12
PRO_0000004572

Sites

Active site1211 By similarity
Active site1631 By similarity

Amino acid modifications

Modified residue261Phosphoserine By similarity
Modified residue1631S-nitrosocysteine; in inhibited form

Natural variations

Natural variant221H → R: dbSNP rs35578277.
VAR_048616
Natural variant1901E → D Ref.6 Ref.1 Ref.3
VAR_001401

Experimental info

Sequence conflict31 – 366ISLDNS → MSWDTG in CAC88866. Ref.3

Secondary structure

1 ............................................ 277
Helix Strand Turn

Details...

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Sequences

Sequence LengthMass (Da)Tools
P42574-1 [UniParc].

Last modified October 11, 2005. Version 2.
Checksum: 2F35CD3BCF7FF64A

FASTA27731,608
        10         20         30         40         50         60 
MENTENSVDS KSIKNLEPKI IHGSESMDSG ISLDNSYKMD YPEMGLCIII NNKNFHKSTG 

        70         80         90        100        110        120 
MTSRSGTDVD AANLRETFRN LKYEVRNKND LTREEIVELM RDVSKEDHSK RSSFVCVLLS 

       130        140        150        160        170        180 
HGEEGIIFGT NGPVDLKKIT NFFRGDRCRS LTGKPKLFII QACRGTELDC GIETDSGVDD 

       190        200        210        220        230        240 
DMACHKIPVE ADFLYAYSTA PGYYSWRNSK DGSWFIQSLC AMLKQYADKL EFMHILTRVN 

       250        260        270 
RKVATEFESF SFDATFHAKK QIPCIVSMLT KELYFYH

« Hide

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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 program
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]Colinge J., Superti-Furga G., Bennett K.L.
Submitted (OCT-2008) to UniProtKB
Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[11]"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.
[12]"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.
[13]"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. expand/collapse author list , Liang P.-H., Janson C.A., McDevitt P.J., Johanson K., Concha N.O., Chan W., Abdel-Meguid S.S., Badger A.M., Lark M.W., Nadeau D.P., Suva L.J., Gowen M., 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.

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Web resources

NIEHS-SNPs

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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.
IPIIPI00292140.
PIRA55315.
RefSeqNP_004337.2.
NP_116786.1.
UniGeneHs.141125

3D structure databases

EntryMethodResolution (Å)ChainPositionsPDBsum
1CP3X-ray2.30A/B1-277[»]
1GFWX-ray2.80A29-175[»]
B181-277[»]
1I3OX-ray2.70A/C1-175[»]
B/D176-277[»]
1NMEX-ray1.60A29-174[»]
B186-277[»]
1NMQX-ray2.40A/B29-277[»]
1NMSX-ray1.70A/B29-277[»]
1PAUX-ray2.50A29-175[»]
B176-277[»]
1QX3X-ray1.90A29-277[»]
1RE1X-ray2.50A29-175[»]
B176-277[»]
1RHJX-ray2.20A/C29-175[»]
B/D176-277[»]
1RHKX-ray2.50A29-175[»]
B176-277[»]
1RHMX-ray2.50A/C29-175[»]
B/D176-277[»]
1RHQX-ray3.00A/D29-175[»]
B/E176-277[»]
1RHRX-ray3.00A29-175[»]
B176-277[»]
1RHUX-ray2.51A29-175[»]
B176-277[»]
2C1EX-ray1.77A29-175[»]
B176-277[»]
2C2KX-ray1.87A29-175[»]
B176-277[»]
2C2MX-ray1.94A29-175[»]
B176-277[»]
2C2OX-ray2.45A29-175[»]
B176-277[»]
2CDRX-ray1.70A29-175[»]
B176-277[»]
2CJXX-ray1.70A29-175[»]
B176-277[»]
2CJYX-ray1.67A29-175[»]
B176-277[»]
2CNKX-ray1.75A29-175[»]
B176-277[»]
2CNLX-ray1.67A29-175[»]
B176-277[»]
2CNNX-ray1.70A29-175[»]
B176-277[»]
2CNOX-ray1.95A29-175[»]
B176-277[»]
2DKOX-ray1.06A29-174[»]
B176-277[»]
2H5IX-ray1.69A29-174[»]
B184-277[»]
2H5JX-ray2.00A/C29-174[»]
B/D184-277[»]
2H65X-ray2.30A/C29-174[»]
B/D184-277[»]
2J30X-ray1.40A29-277[»]
2J31X-ray1.50A29-277[»]
2J32X-ray1.30A29-277[»]
2J33X-ray2.00A29-277[»]
3DEHX-ray2.50A/B/C/D29-277[»]
3DEIX-ray2.80A/B/C/D29-277[»]
3DEJX-ray2.60A/B/C/D29-277[»]
3DEKX-ray2.40A/B/C/D29-277[»]
3EDQX-ray1.61A/C29-175[»]
B176-277[»]
D180-277[»]
3GJQX-ray2.60A/C29-175[»]
B/D176-277[»]
3GJRX-ray2.20A/C29-175[»]
B/D176-277[»]
3GJSX-ray1.90A/C29-175[»]
B/D176-277[»]
3GJTX-ray2.20A/C29-175[»]
B/D176-277[»]
ModBaseSearch...

Protein-protein interaction databases

DIPDIP:268N.
DIP:434N.
IntActP42574. 5 interactions.

Protein family/group databases

MEROPSC14.003.

PTM databases

PhosphoSiteP42574.

2-D gel databases

OGPP42574.

Proteomic databases

PeptideAtlasP42574.
PRIDEP42574.

Genome annotation databases

EnsemblENSG00000164305. Homo sapiens. [Contig view]
GeneID836.
KEGGhsa:836.

Organism-specific databases

GeneCardsGC04M185785.
H-InvDBHIX0004672.
HGNCHGNC:1504. CASP3.
HPACAB000091.
CAB008381.
HPA002643.
MIM600636. gene.
PharmGKBPA26087.
GenAtlasSearch...

Phylogenomic databases

HOGENOMP42574.
HOVERGENP42574.
OMAP42574. HGEEGII.

Enzyme and pathway databases

BRENDA3.4.22.56. 247.
Pathway_Interaction_DBa6b1_a6b4_integrin_pathway. a6b1 and a6b4 Integrin signaling.
nfat_tfpathway. Calcineurin-regulated NFAT-dependent transcription in lymphocytes.
caspase_pathway. Caspase cascade in apoptosis.
faspathway. FAS signaling pathway (CD95).
hivnefpathway. HIV-1 Nef: Negative effector of Fas and TNF-alpha.
lysophospholipid_pathway. LPA receptor mediated events.
p75ntrpathway. p75(NTR)-mediated signaling.
nfat_3pathway. Role of Calcineurin-dependent NFAT signaling in lymphocytes.
syndecan_2_pathway. Syndecan-2-mediated signaling events.
ReactomeREACT_11061. Signalling by NGF.
REACT_578. Apoptosis.

Gene expression databases

ArrayExpressP42574.
BgeeP42574.
CleanExHS_CASP3.
GermOnlineENSG00000164305. Homo sapiens.

Family and domain databases

InterProIPR015470. Caspase_3_related.
IPR011600. Pept_C14_cat.
IPR001309. Pept_C14_ICE_p20.
IPR016129. Pept_C14_ICE_p20_AS.
IPR002138. Pept_C14_p10.
IPR002398. Pept_C14_p45.
IPR015917. Pept_C14_p45_core.
[Graphical view]
PANTHERPTHR10454:SF30. Casp3_like. 1 hit.
PTHR10454. Pept_C14_p45. 1 hit.
PfamPF00656. Peptidase_C14. 1 hit.
[Graphical view]
PRINTSPR00376. IL1BCENZYME.
SMARTSM00115. CASc. 1 hit.
[Graphical view]
PROSITEPS01122. CASPASE_CYS. 1 hit.
PS01121. CASPASE_HIS. 1 hit.
PS50207. CASPASE_P10. 1 hit.
PS50208. CASPASE_P20. 1 hit.
[Graphical view]
ProtoNetSearch...

Other Resources

BindingDBP42574.
DrugBankDB01065. Melatonin.
DB01017. Minocycline.
DB00641. Simvastatin.
NextBio3478.
PMAP-CutDBP42574.
SOURCESearch...

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Entry information

Entry nameCASP3_HUMAN
AccessionPrimary (citable) accession number: P42574
Secondary accession number(s): Q96AN1, Q96KP2
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: October 11, 2005
Last modified: June 16, 2009
This is version 118 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation projectHPI (Human Proteome Initiative)

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Index of Protein Data Bank (PDB) cross-references

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents