[1]	NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ASP-190. TISSUE=T-cell; PubMed=7983002 [NCBI, ExPASy, EBI, Israel, Japan] Fernandes-Alnemri T., Litwack G., Alnemri E.S.; "CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme."; J. Biol. Chem. 269:30761-30764(1994).
[2]	NUCLEOTIDE SEQUENCE [MRNA]. DOI=10.1016/0092-8674(95)90541-3; PubMed=7774019 [NCBI, ExPASy, EBI, Israel, Japan] Tewari M., Quan L.T., O'Rourke K., Desnoyers S., Zeng Z., Beidler D.R., Poirier G.G., Salvesen G.S., Dixit V.M.; "Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase."; Cell 81:801-809(1995).
[3]	NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ASP-190. DOI=10.1016/j.bbrc.2004.02.021; PubMed=15003516 [NCBI, ExPASy, EBI, Israel, Japan] Pelletier M., Cartron P.F., Delaval F., Meflah K., Vallette F.M., Oliver L.; "Caspase 3 activation is controlled by a sequence located in the N-terminus of its large subunit."; Biochem. Biophys. Res. Commun. 316:93-99(2004).
[4]	NUCLEOTIDE SEQUENCE [GENOMIC DNA]. NIEHS SNPs program; Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases.
[5]	NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. TISSUE=Lymph; DOI=10.1101/gr.2596504; PubMed=15489334 [NCBI, ExPASy, EBI, Israel, Japan] The MGC Project Team; "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."; Genome Res. 14:2121-2127(2004).
[6]	PROTEIN SEQUENCE OF 29-46 AND 175-193, FUNCTION, AND VARIANT ASP-190. DOI=10.1038/376037a0; PubMed=7596430 [NCBI, ExPASy, EBI, Israel, Japan] 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.; "Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis."; Nature 376:37-43(1995).
[7]	PROTEOLYTIC PROCESSING. DOI=10.1073/pnas.93.15.7464; PubMed=8755496 [NCBI, ExPASy, EBI, Israel, Japan] 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.; "In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains."; Proc. Natl. Acad. Sci. U.S.A. 93:7464-7469(1996).
[8]	CLEAVAGE OF HUNTINGTIN. DOI=10.1038/ng0896-442; PubMed=8696339 [NCBI, ExPASy, EBI, Israel, Japan] 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.; "Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract."; Nat. Genet. 13:442-449(1996).
[9]	S-NITROSYLATION. DOI=10.1126/science.284.5414.651; PubMed=10213689 [NCBI, ExPASy, EBI, Israel, Japan] Mannick J.B., Hausladen A., Liu L., Hess D.T., Zeng M., Miao Q.X., Kane L.S., Gow A.J., Stamler J.S.; "Fas-induced caspase denitrosylation."; Science 284:651-654(1999).
[10]	IDENTIFICATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY. Colinge J., Superti-Furga G., Bennett K.L.; Submitted (OCT-2008) to UniProtKB.
[11]	X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 28-277. DOI=10.1038/nsb0796-619; PubMed=8673606 [NCBI, ExPASy, EBI, Israel, Japan] 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.; "The three-dimensional structure of apopain/CPP32, a key mediator of apoptosis."; Nat. Struct. Biol. 3:619-625(1996).
[12]	X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 35-173 AND 185-277. DOI=10.1074/jbc.272.10.6539; PubMed=9045680 [NCBI, ExPASy, EBI, Israel, Japan] Mittl P.R.E., di Marco S., Krebs J.F., Bai X., Karanewsky D.S., Priestle J.P., Tomaselli K.J., Gruetter M.G.; "Structure of recombinant human CPP32 in complex with the tetrapeptide acetyl-Asp-Val-Ala-Asp fluoromethyl ketone."; J. Biol. Chem. 272:6539-6547(1997).
[13]	X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS). DOI=10.1074/jbc.275.21.16007; PubMed=10821855 [NCBI, ExPASy, EBI, Israel, Japan] 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., 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.; "Potent and selective nonpeptide inhibitors of caspases 3 and 7 inhibit apoptosis and maintain cell functionality."; J. Biol. Chem. 275:16007-16014(2000).

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: Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 17 kDa (p17) and a 12 kDa (p12) subunit.
INTERACTION:
Q13490:BIRC2; NbExp=1; IntAct=EBI-524064, EBI-514538;
Q96CA5:BIRC7; NbExp=1; IntAct=EBI-524064, EBI-517623;
Q9BYP7:WNK3; NbExp=2; IntAct=EBI-524064, EBI-1182602;
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.
PTM: 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.
PTM: 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.
SIMILARITY: Belongs to the peptidase C14A family [view classification].
WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/casp3/";.

Copyright

Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms. Distributed under the Creative Commons Attribution-NoDerivs License.

Cross-references

Sequence databases

EMBL

U13737; AAA65015.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
U13738; AAB60355.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
U26943; AAA74929.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AJ413269; CAC88866.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AY219866; AAO25654.1; -; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
BC016926; AAH16926.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]

IPI

IPI00292140; -.

PIR

A55315; A55315.

RefSeq

NP_004337.2; -.
NP_116786.1; -.

UniGene

Hs.141125

3D structure databases

PDB

1CP3; X-ray; 2.30 A; A/B=1-277.	[ExPASy / RCSB / EBI]
1GFW; X-ray; 2.80 A; A=29-175, B=181-277.	[ExPASy / RCSB / EBI]
1I3O; X-ray; 2.70 A; A/C=1-175, B/D=176-277.	[ExPASy / RCSB / EBI]
1NME; X-ray; 1.60 A; A=29-174, B=186-277.	[ExPASy / RCSB / EBI]
1NMQ; X-ray; 2.40 A; A/B=29-277.	[ExPASy / RCSB / EBI]
1NMS; X-ray; 1.70 A; A/B=29-277.	[ExPASy / RCSB / EBI]
1PAU; X-ray; 2.50 A; A=29-175, B=176-277.	[ExPASy / RCSB / EBI]
1QX3; X-ray; 1.90 A; A=29-277.	[ExPASy / RCSB / EBI]
1RE1; X-ray; 2.50 A; A=29-175, B=176-277.	[ExPASy / RCSB / EBI]
1RHJ; X-ray; 2.20 A; A/C=29-175, B/D=176-277.	[ExPASy / RCSB / EBI]
1RHK; X-ray; 2.50 A; A=29-175, B=176-277.	[ExPASy / RCSB / EBI]
1RHM; X-ray; 2.50 A; A/C=29-175, B/D=176-277.	[ExPASy / RCSB / EBI]
1RHQ; X-ray; 3.00 A; A/D=29-175, B/E=176-277.	[ExPASy / RCSB / EBI]
1RHR; X-ray; 3.00 A; A=29-175, B=176-277.	[ExPASy / RCSB / EBI]
1RHU; X-ray; 2.51 A; A=29-175, B=176-277.	[ExPASy / RCSB / EBI]
2C1E; X-ray; 1.77 A; A=29-175, B=176-277.	[ExPASy / RCSB / EBI]
2C2K; X-ray; 1.87 A; A=29-175, B=176-277.	[ExPASy / RCSB / EBI]
2C2M; X-ray; 1.94 A; A=29-175, B=176-277.	[ExPASy / RCSB / EBI]
2C2O; X-ray; 2.45 A; A=29-175, B=176-277.	[ExPASy / RCSB / EBI]
2CDR; X-ray; 1.70 A; A=29-175, B=176-277.	[ExPASy / RCSB / EBI]
2CJX; X-ray; 1.70 A; A=29-175, B=176-277.	[ExPASy / RCSB / EBI]
2CJY; X-ray; 1.67 A; A=29-175, B=176-277.	[ExPASy / RCSB / EBI]
2CNK; X-ray; 1.75 A; A=29-175, B=176-277.	[ExPASy / RCSB / EBI]
2CNL; X-ray; 1.67 A; A=29-175, B=176-277.	[ExPASy / RCSB / EBI]
2CNN; X-ray; 1.70 A; A=29-175, B=176-277.	[ExPASy / RCSB / EBI]
2CNO; X-ray; 1.95 A; A=29-175, B=176-277.	[ExPASy / RCSB / EBI]
2DKO; X-ray; 1.06 A; A=29-174, B=176-277.	[ExPASy / RCSB / EBI]
2H5I; X-ray; 1.69 A; A=29-174, B=184-277.	[ExPASy / RCSB / EBI]
2H5J; X-ray; 2.00 A; A/C=29-174, B/D=184-277.	[ExPASy / RCSB / EBI]
2H65; X-ray; 2.30 A; A/C=29-174, B/D=184-277.	[ExPASy / RCSB / EBI]
2J30; X-ray; 1.40 A; A=29-277.	[ExPASy / RCSB / EBI]
2J31; X-ray; 1.50 A; A=29-277.	[ExPASy / RCSB / EBI]
2J32; X-ray; 1.30 A; A=29-277.	[ExPASy / RCSB / EBI]
2J33; X-ray; 2.00 A; A=29-277.	[ExPASy / RCSB / EBI]
3DEH; X-ray; 2.50 A; A/B/C/D=29-277.	[ExPASy / RCSB / EBI]
3DEI; X-ray; 2.80 A; A/B/C/D=29-277.	[ExPASy / RCSB / EBI]
3DEJ; X-ray; 2.60 A; A/B/C/D=29-277.	[ExPASy / RCSB / EBI]
3DEK; X-ray; 2.40 A; A/B/C/D=29-277.	[ExPASy / RCSB / EBI]
3EDQ; X-ray; 1.61 A; A/C=29-175, B=176-277, D=180-277.	[ExPASy / RCSB / EBI]
3GJQ; X-ray; 2.60 A; A/C=29-175, B/D=176-277.	[ExPASy / RCSB / EBI]
3GJR; X-ray; 2.20 A; A/C=29-175, B/D=176-277.	[ExPASy / RCSB / EBI]
3GJS; X-ray; 1.90 A; A/C=29-175, B/D=176-277.	[ExPASy / RCSB / EBI]
3GJT; X-ray; 2.20 A; A/C=29-175, B/D=176-277.	[ExPASy / RCSB / EBI]

Detailed list of linked structures.

PDBsum

1CP3; -.
1GFW; -.
1I3O; -.
1NME; -.
1NMQ; -.
1NMS; -.
1PAU; -.
1QX3; -.
1RE1; -.
1RHJ; -.
1RHK; -.
1RHM; -.
1RHQ; -.
1RHR; -.
1RHU; -.
2C1E; -.
2C2K; -.
2C2M; -.
2C2O; -.
2CDR; -.
2CJX; -.
2CJY; -.
2CNK; -.
2CNL; -.
2CNN; -.
2CNO; -.
2DKO; -.
2H5I; -.
2H5J; -.
2H65; -.
2J30; -.
2J31; -.
2J32; -.
2J33; -.
3DEH; -.
3DEI; -.
3DEJ; -.
3DEK; -.
3EDQ; -.
3GJQ; -.
3GJR; -.
3GJS; -.
3GJT; -.

ModBase

P42574.

Protein-protein interaction databases

DIP

DIP:268N; -.
DIP:434N; -.

IntAct

P42574; 5.

Protein family/group databases

MEROPS

C14.003; -.

PTM databases

PhosphoSite

P42574; -.

Enzyme and pathway databases

BRENDA

3.4.22.56; 247.

Pathway_Interaction_DB

a6b1_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.

Reactome

REACT_11061; Signalling by NGF.
REACT_578; Apoptosis.

2D gel databases

OGP

P42574; -.

Organism-specific databases

GC04M185785; -.

HIX0004672; -.

HGNC:1504; CASP3.

CAB000091; -.
CAB008381; -.
HPA002643; -.

MIM

600636; gene. [NCBI / EBI]

PharmGKB

PA26087; -.

Gene expression databases

P42574; -.

P42574; -.

HS_CASP3; -.

ENSG00000164305; Homo sapiens.

Ontologies

GO:0005829;	Cellular component: cytosol (inferred from direct assay from UniProtKB).
GO:0005739;	Cellular component: mitochondrion (inferred from direct assay from HPA).
GO:0005654;	Cellular component: nucleoplasm (inferred from experiment from Reactome).
GO:0005886;	Cellular component: plasma membrane (inferred from experiment from Reactome).
GO:0030693;	Molecular function: caspase activity (inferred from experiment from Reactome).
GO:0004197;	Molecular function: cysteine-type endopeptidase activity (traceable author statement from ProtInc).
GO:0005515;	Molecular function: protein binding (inferred from physical interaction from UniProtKB).
GO:0043066;	Biological process: negative regulation of apoptosis (inferred from genetic interaction from MGI).
GO:0030264;	Biological process: nuclear fragmentation during apoptosis (inferred from mutant phenotype from HGNC).
GO:0006508;	Biological process: proteolysis (inferred from direct assay from UniProtKB).
GO:0034612;	Biological process: response to tumor necrosis factor (traceable author statement from UniProtKB).
QuickGo view.

Family and domain databases

InterPro

IPR015470; 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 of domain structure.

PANTHER

PTHR10454:SF30; Casp3_like; 1.
PTHR10454; Pept_C14_p45; 1.

Pfam

PF00656; Peptidase_C14; 1.
Pfam graphical view of domain structure.

PRINTS

PR00376; IL1BCENZYME.

SMART

SM00115; CASc; 1.
SMART graphical view of domain structure.

PROSITE

PS01122; CASPASE_CYS; 1.
PS01121; CASPASE_HIS; 1.
PS50207; CASPASE_P10; 1.
PS50208; CASPASE_P20; 1.
PROSITE graphical view of domain structure (profiles).

Proteomic databases

PeptideAtlas

P42574; -.

PRIDE

P42574; -.

Genome annotation databases

Ensembl

ENSG00000164305; Homo sapiens. [Contig view]

GeneID

836; -.

KEGG

hsa:836; -.

Phylogenomic databases

HOGENOM

P42574; -.

HOVERGEN

P42574; -.

OMA

P42574; HGEEGII.

Other

BindingDB

P42574; -.

DrugBank

DB01065; Melatonin.
DB01017; Minocycline.
DB00641; Simvastatin.

3478; -.

P42574; -.

CASP3; Homo sapiens.

View cluster of proteins with at least 50% / 90% / 100% identity.

Keywords

3D-structure; Apoptosis; Cytoplasm; Direct protein sequencing; Hydrolase; Phosphoprotein; Polymorphism; Protease; S-nitrosylation; Thiol protease; Zymogen.

Features

Feature table viewer

Feature aligner

`Key`	`From To`	`Length`	`Description`	`FTId`
`PROPEP`	`1 9`	`9`		`PRO_0000004569`
`PROPEP`	`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`
`ACT_SITE`	`121 121`		`By similarity.`
`ACT_SITE`	`163 163`		`By similarity.`
`MOD_RES`	`26 26`		`Phosphoserine (By similarity).`
`MOD_RES`	`163 163`		`S-nitrosocysteine; in inhibited form.`
`VARIANT`	`22 22`	`1`	`H -> R (in dbSNP:rs35578277 [NCBI]).`	`VAR_048616`
`VARIANT`	`190 190`	`1`	`E -> D.`	`VAR_001401`
`CONFLICT`	`31 36`		`ISLDNS -> MSWDTG (in Ref. 3; CAC88866).`
`STRAND`	`41 51`	`11`
`HELIX`	`57 59`	`3`
`HELIX`	`67 80`	`14`
`STRAND`	`84 90`	`7`
`HELIX`	`93 105`	`13`
`STRAND`	`111 120`	`10`
`STRAND`	`126 129`	`4`
`STRAND`	`132 135`	`4`
`HELIX`	`136 141`	`6`
`TURN`	`145 147`	`3`
`HELIX`	`149 151`	`3`
`STRAND`	`156 162`	`7`
`STRAND`	`165 167`	`3`
`TURN`	`189 192`	`4`
`STRAND`	`193 199`	`7`
`STRAND`	`206 208`	`3`
`TURN`	`209 211`	`3`
`HELIX`	`214 226`	`13`
`TURN`	`227 229`	`3`
`HELIX`	`232 246`	`15`
`HELIX`	`254 256`	`3`
`STRAND`	`264 267`	`4`
`STRAND`	`270 272`	`3`
`STRAND`	`275 277`	`3`

Sequence information

Length: 277 AA [This is the length of the unprocessed precursor]

Molecular weight: 31608 Da [This is the MW of the unprocessed precursor]

CRC64: 2F35CD3BCF7FF64A [This is a checksum on the sequence]

        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

P42574 in FASTA format

View entry in raw text format (no links)
Report form for errors/updates in this UniProtKB/Swiss-Prot entry

	BLAST submission on ExPASy/SIB or at NCBI (USA)		Sequence analysis tools: ProtParam, ProtScale, Compute pI/Mw, PeptideMass, PeptideCutter, Dotlet (Java)
	ScanProsite, MotifScan		Submit a homology modeling request to SWISS-MODEL
	NPSA Sequence analysis tools