Reviewed, UniProtKB/Swiss-Prot P42574 (CASP3_HUMAN)

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

Name:	CASP3
Synonyms:	CPP32

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	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 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 apoptosis Inferred from mutant phenotype. Source: HGNC proteolysis Inferred from direct assay. Source: UniProtKB
Cellular component	cytosol Inferred from direct assay. Source: UniProtKB mitochondrion Inferred from direct assay. Source: HPA nucleoplasm Inferred from Experiment. Source: Reactome plasma membrane Inferred from Experiment. Source: Reactome
Molecular function	cysteine-type endopeptidase activity Traceable author statement. Source: ProtInc protein binding Inferred 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

1

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277

Helix Strand Turn

Details...

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

	Sequence		Length	Mass (Da)
	P42574-1 [UniParc]. Last modified October 11, 2005. Version 2. Checksum: 2F35CD3BCF7FF64A	FASTA	277	31,608
	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

References

	« Hide 'large scale' referencesShow '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. , 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.

Cross-references

Sequence databases

EMBLGenBankDDBJ

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

PDBMSD

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1CP3	X-ray	2.30	A/B	1-277	[»]
1GFW	X-ray	2.80	A	29-175	[»]
			B	181-277	[»]
1I3O	X-ray	2.70	A/C	1-175	[»]
			B/D	176-277	[»]
1NME	X-ray	1.60	A	29-174	[»]
			B	186-277	[»]
1NMQ	X-ray	2.40	A/B	29-277	[»]
1NMS	X-ray	1.70	A/B	29-277	[»]
1PAU	X-ray	2.50	A	29-175	[»]
			B	176-277	[»]
1QX3	X-ray	1.90	A	29-277	[»]
1RE1	X-ray	2.50	A	29-175	[»]
			B	176-277	[»]
1RHJ	X-ray	2.20	A/C	29-175	[»]
			B/D	176-277	[»]
1RHK	X-ray	2.50	A	29-175	[»]
			B	176-277	[»]
1RHM	X-ray	2.50	A/C	29-175	[»]
			B/D	176-277	[»]
1RHQ	X-ray	3.00	A/D	29-175	[»]
			B/E	176-277	[»]
1RHR	X-ray	3.00	A	29-175	[»]
			B	176-277	[»]
1RHU	X-ray	2.51	A	29-175	[»]
			B	176-277	[»]
2C1E	X-ray	1.77	A	29-175	[»]
			B	176-277	[»]
2C2K	X-ray	1.87	A	29-175	[»]
			B	176-277	[»]
2C2M	X-ray	1.94	A	29-175	[»]
			B	176-277	[»]
2C2O	X-ray	2.45	A	29-175	[»]
			B	176-277	[»]
2CDR	X-ray	1.70	A	29-175	[»]
			B	176-277	[»]
2CJX	X-ray	1.70	A	29-175	[»]
			B	176-277	[»]
2CJY	X-ray	1.67	A	29-175	[»]
			B	176-277	[»]
2CNK	X-ray	1.75	A	29-175	[»]
			B	176-277	[»]
2CNL	X-ray	1.67	A	29-175	[»]
			B	176-277	[»]
2CNN	X-ray	1.70	A	29-175	[»]
			B	176-277	[»]
2CNO	X-ray	1.95	A	29-175	[»]
			B	176-277	[»]
2DKO	X-ray	1.06	A	29-174	[»]
			B	176-277	[»]
2H5I	X-ray	1.69	A	29-174	[»]
			B	184-277	[»]
2H5J	X-ray	2.00	A/C	29-174	[»]
			B/D	184-277	[»]
2H65	X-ray	2.30	A/C	29-174	[»]
			B/D	184-277	[»]
2J30	X-ray	1.40	A	29-277	[»]
2J31	X-ray	1.50	A	29-277	[»]
2J32	X-ray	1.30	A	29-277	[»]
2J33	X-ray	2.00	A	29-277	[»]
3DEH	X-ray	2.50	A/B/C/D	29-277	[»]
3DEI