Reviewed, UniProtKB/Swiss-Prot P42575 (CASP2_HUMAN)

Names and origin

Protein names

Recommended name:
    Caspase-2
      Short name=CASP-2
    EC=3.4.22.55
Alternative name(s):
    ICH-1 protease
    Neural precursor cell expressed developmentally down-regulated protein 2
      Short name=NEDD-2
Cleaved into the following 3 chains:
    1- Recommended name:
            Caspase-2 subunit p18
    2- Recommended name:
            Caspase-2 subunit p13
    3- Recommended name:
            Caspase-2 subunit p12

Gene names

Name:	CASP2
Synonyms:	ICH1, NEDD2

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	452 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. Might function by either activating some proteins required for cell death or inactivating proteins necessary for cell survival.
Catalytic activity	Strict requirement for an Asp residue at P1, with 316-asp being essential for proteolytic activity and has a preferred cleavage sequence of Val-Asp-Val-Ala-Asp-|-.
Subunit structure	Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a p18 subunit and a p12 subunit. Interacts with LRDD. Ref.10 Ref.11 Ref.12
Tissue specificity	Expressed at higher levels in the embryonic lung, liver and kidney than in the heart and brain. In adults, higher level expression is seen in the placenta, lung, kidney, and pancreas than in the heart, brain, liver and skeletal muscle.
Post-translational modification	The mature protease can process its own propeptide, but not that of other caspases.
Sequence similarities	Belongs to the peptidase C14A family. Contains 1 CARD domain.

Ontologies

Keywords
Biological process	Apoptosis
Coding sequence diversity	Alternative splicing Polymorphism
Molecular function	Hydrolase Protease Thiol protease
PTM	Zymogen
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	apoptosis Ref.7 Non-traceable author statement. Source: UniProtKB protein maturation by peptide bond cleavage Inferred from direct assay. Source: UniProtKB proteolysis Inferred from electronic annotation. Source: InterPro regulation of apoptosis Inferred from electronic annotation. Source: InterPro
Cellular component	intracellular Inferred from electronic annotation. Source: InterPro
Molecular function	cysteine-type endopeptidase activity Inferred from direct assay. Source: UniProtKB enzyme binding Inferred from sequence or structural similarity. Source: UniProtKB identical protein binding Ref.7 Inferred from physical interaction. Source: IntAct protein domain specific binding Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CASP2	P42575	1	EBI-520357,EBI-520342
CASP2	P42575-1	1	EBI-520342,EBI-520357
CRADD	P78560	3	EBI-520342,EBI-520375

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Note: Isoforms differ in the N- and C-termini.

Isoform ICH-1L (identifier: P42575-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Note: Acts as a positive regulator of apoptosis.

Isoform ICH-1S (identifier: P42575-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-31: Missing.
     323-452: DETDRGVDQQ...LYLFPGHPPT → GGAIGSLGHLLLFTAATASLAL

Note: Acts as a negative regulator of apoptosis.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Propeptide

1 – 169

169

PRO_0000004541

Chain

170 – 325

156

Caspase-2 subunit p18

PRO_0000004542

Propeptide

326 – 333

8

PRO_0000004543

Chain

334 – 452

119

Caspase-2 subunit p13

PRO_0000004544

Chain

348 – 452

105

Caspase-2 subunit p12

PRO_0000004545

Regions

Domain

32 – 120

89

CARD

Sites

Active site

277

1

By similarity

Active site

320

1

By similarity

Natural variations

Alternative sequence

1 – 31

31

Missing in isoform ICH-1S.

VSP_000801

Alternative sequence

323 – 452

130

DETDR…GHPPT → GGAIGSLGHLLLFTAATASL AL in isoform ICH-1S.

VSP_000802

Natural variant

105

1

A → G: dbSNP rs4647298.

VAR_055621

Natural variant

172

1

V → L: dbSNP rs4647297. Ref.3 Ref.5 Ref.6

VAR_016334

Natural variant

178

1

P → A: dbSNP rs4647298. Ref.3

VAR_016335

Natural variant

441

1

R → G: dbSNP rs4647338. Ref.3

VAR_016336

Experimental info

Mutagenesis

320

1

C → S: Loss of function.

Mutagenesis

369

1

A → T: Loss of function.

Sequence conflict

107 – 108

2

RE → HS in AAK00300. Ref.7

Sequence conflict

309 – 322

14

QNKPK…QACRG → EEVTSLSILSAFVT in BAD92877. Ref.8

Secondary structure

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452

Helix Strand Turn

Details...

Helix

181 – 187

7

Helix

188 – 190

3

Beta strand

197 – 206

10

Beta strand

212 – 214

3

Helix

222 – 235

14

Beta strand

238 – 245

8

Helix

248 – 259

12

Helix

262 – 265

4

Beta strand

267 – 276

10

Beta strand

282 – 284

3

Beta strand

290 – 292

3

Helix

293 – 299

7

Turn

302 – 304

3

Helix

306 – 308

3

Beta strand

313 – 319

7

Beta strand

321 – 324

4

Beta strand

363 – 370

8

Beta strand

377 – 379

3

Turn

380 – 382

3

Helix

385 – 397

13

Turn

398 – 400

3

Helix

403 – 415

13

Turn

425 – 428

4

Beta strand

434 – 437

4

Sequences

	Sequence		Length	Mass (Da)
	Isoform ICH-1L [UniParc]. Last modified December 6, 2005. Version 2. Checksum: 6EF0ED05EF808385	FASTA	452	50,685
	10 20 30 40 50 60 MAAPSAGSWS TFQHKELMAA DRGRRILGVC GMHPHHQETL KKNRVVLAKQ LLLSELLEHL 70 80 90 100 110 120 LEKDIITLEM RELIQAKVGS FSQNVELLNL LPKRGPQAFD AFCEALRETK QGHLEDMLLT 130 140 150 160 170 180 TLSGLQHVLP PLSCDYDLSL PFPVCESCPL YKKLRLSTDT VEHSLDNKDG PVCLQVKPCT 190 200 210 220 230 240 PEFYQTHFQL AYRLQSRPRG LALVLSNVHF TGEKELEFRS GGDVDHSTLV TLFKLLGYDV 250 260 270 280 290 300 HVLCDQTAQE MQEKLQNFAQ LPAHRVTDSC IVALLSHGVE GAIYGVDGKL LQLQEVFQLF 310 320 330 340 350 360 DNANCPSLQN KPKMFFIQAC RGDETDRGVD QQDGKNHAGS PGCEESDAGK EKLPKMRLPT 370 380 390 400 410 420 RSDMICGYAC LKGTAAMRNT KRGSWYIEAL AQVFSERACD MHVADMLVKV NALIKDREGY 430 440 450 APGTEFHRCK EMSEYCSTLC RHLYLFPGHP PT
	Isoform ICH-1S. Checksum: FA1E307A41B8299E	FASTA	313	34,923
	10 20 30 40 50 60 MHPHHQETLK KNRVVLAKQL LLSELLEHLL EKDIITLEMR ELIQAKVGSF SQNVELLNLL 70 80 90 100 110 120 PKRGPQAFDA FCEALRETKQ GHLEDMLLTT LSGLQHVLPP LSCDYDLSLP FPVCESCPLY 130 140 150 160 170 180 KKLRLSTDTV EHSLDNKDGP VCLQVKPCTP EFYQTHFQLA YRLQSRPRGL ALVLSNVHFT 190 200 210 220 230 240 GEKELEFRSG GDVDHSTLVT LFKLLGYDVH VLCDQTAQEM QEKLQNFAQL PAHRVTDSCI 250 260 270 280 290 300 VALLSHGVEG AIYGVDGKLL QLQEVFQLFD NANCPSLQNK PKMFFIQACR GGGAIGSLGH 310 LLLFTAATAS LAL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Ich-1, an Ice/ced-3-related gene, encodes both positive and negative regulators of programmed cell death." Wang L., Miura M., Bergeron L., Zhu H., Yuan J. Cell 78:739-750(1994) [PubMed: 8087842] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ICH-1S), NUCLEOTIDE SEQUENCE [MRNA] OF 14-452 (ISOFORM ICH-1L). Tissue: Fetal brain.
[2]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S., Neubert P., Kstrang K., Schatten R., Shen B., Henze S., Mar W., Korn B., Zuo D., Hu Y., LaBaer J. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM ICH-1S).
[3]	NIEHS SNPs program Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS LEU-172; ALA-178 AND GLY-441.
[4]	"The DNA sequence of human chromosome 7." Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., Delehaunty K.D., Miner T.L. , Nash W.E., Cordes M., Du H., Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., Wilson R.K. Nature 424:157-164(2003) [PubMed: 12853948] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE 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] (ISOFORM ICH-1L), VARIANT LEU-172. Tissue: Skin.
[6]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 18-452 (ISOFORM 1), VARIANT LEU-172.
[7]	"Identification of a caspase-2 isoform that behaves as an endogenous inhibitor of the caspase cascade." Droin N., Beauchemin M., Solary E., Bertrand R. Cancer Res. 60:7039-7047(2000) [PubMed: 11156409] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 32-108 (ISOFORMS 1/2).
[8]	Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., Ohara O., Nagase T., Kikuno R.F. Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 194-452. Tissue: Spleen.
[9]	"The Caenorhabditis elegans cell-death protein CED-3 is a cysteine protease with substrate specificities similar to those of the human CPP32 protease." Xue D., Shaham S., Horvitz H.R. Genes Dev. 10:1073-1083(1996) [PubMed: 8654923] [Abstract] Cited for: CLEAVAGE SITES.
[10]	"The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress." Tinel A., Tschopp J. Science 304:843-846(2004) [PubMed: 15073321] [Abstract] Cited for: INTERACTION WITH LRDD.
[11]	"Functional connection between p53 and caspase-2 is essential for apoptosis induced by DNA damage." Vakifahmetoglu H., Olsson M., Orrenius S., Zhivotovsky B. Oncogene 25:5683-5692(2006) [PubMed: 16652156] [Abstract] Cited for: INTERACTION WITH LRDD.
[12]	"Crystal structure of caspase-2, apical initiator of the intrinsic apoptotic pathway." Schweizer A., Briand C., Grutter M.G. J. Biol. Chem. 278:42441-42447(2003) [PubMed: 12920126] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 167-452 IN COMPLEX WITH INHIBITOR, SUBUNIT, DISULFIDE BOND.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

Cross-references

Sequence databases

EMBLGenBankDDBJ

U13021 mRNA. Translation: AAA58959.1. Different initiation.
U13022 mRNA. Translation: AAA58960.1.
CR541748 mRNA. Translation: CAG46548.1.
AY219042 Genomic DNA. Translation: AAO25653.1. Different initiation.
AC073342 Genomic DNA. Translation: AAP22346.1. Different initiation.
AC073342 Genomic DNA. Translation: AAP22347.1.
AC073342 Genomic DNA. Translation: AAP22349.1. Different initiation.
BC002427 mRNA. Translation: AAH02427.2.
BT007240 mRNA. Translation: AAP35904.1.
AF314175 mRNA. Translation: AAK00300.1.
AB209640 mRNA. Translation: BAD92877.1. Different initiation.

IPI

IPI00216410.
IPI00291570.

PIR

A54821.

RefSeq

NP_116764.2.

UniGene

Hs.368982

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1PYO	X-ray	1.65	A/C	167-333	[»]
			B/D	348-452	[»]
2P2C	X-ray	3.24	A/C/E/G/I/K	167-333	[»]
			B/D/F/H/J/L	348-452	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

P42575. 4 interactions.

Protein family/group databases

MEROPS

C14.006.

PTM databases

PhosphoSite

P42575.

Proteomic databases

PeptideAtlas

P42575.

PRIDE

P42575.

Genome annotation databases

Ensembl

ENSG00000106144. Homo sapiens. [Contig view]

GeneID

835.

KEGG

hsa:835.

UCSC

uc003wco.1. human.

Organism-specific databases

GeneCards

GC07P142695.

H-InvDB

HIX0007169.

HGNC

HGNC:1503. CASP2.

HPA

CAB012175.

MIM

600639. gene.

PharmGKB

PA26086.

GenAtlas

Search...

Phylogenomic databases

HOVERGEN

P42575.

OMA

P42575. FRLFDNA.

Enzyme and pathway databases

BRENDA

3.4.22.55. 247.

Pathway_Interaction_DB

caspase_pathway. Caspase cascade in apoptosis.
hivnefpathway. HIV-1 Nef: Negative effector of Fas and TNF-alpha.

Reactome

REACT_11061. Signalling by NGF.

Gene expression databases

ArrayExpress

P42575.

Bgee

P42575.

CleanEx

HS_CASP2.

GermOnline

ENSG00000106144. Homo sapiens.

Family and domain databases

InterPro

IPR001315. CARD.
IPR017350. Caspase_IL-1_beta.
IPR011029. DEATH-like.
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]

Gene3D

G3DSA:1.10.533.10. DEATH_like. 1 hit.

PANTHER

PTHR10454. Pept_C14_p45. 1 hit.

Pfam

PF00619. CARD. 1 hit.
PF00656. Peptidase_C14. 1 hit.
[Graphical view]

PIRSF

PIRSF038001. Caspase_ICE. 1 hit.

PRINTS

PR00376. IL1BCENZYME.

SMART

SM00114. CARD. 1 hit.
SM00115. CASc. 1 hit.
[Graphical view]

PROSITE

PS50209. CARD. 1 hit.
PS01122. CASPASE_CYS. 1 hit.
PS01121. CASPASE_HIS. 1 hit.
PS50207. CASPASE_P10. 1 hit.
PS50208. CASPASE_P20. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

3472.

PMAP-CutDB

P42575.

SOURCE

Search...

Entry information

Entry name

CASP2_HUMAN

Accession

Primary (citable) accession number: P42575
Secondary accession number(s): P42576 , Q59F21, Q7KZL6, Q86UJ3, Q9BUP7, Q9BZK9

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1995
Last sequence update:	December 6, 2005
Last modified:	July 7, 2009
This is version 99 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)