Reviewed, UniProtKB/Swiss-Prot P55211 (CASP9_HUMAN)

Names and origin

Protein names

Recommended name:
    Caspase-9
      Short name=CASP-9
    EC=3.4.22.62
Alternative name(s):
    ICE-like apoptotic protease 6
      Short name=ICE-LAP6
    Apoptotic protease Mch-6
    Apoptotic protease-activating factor 3
      Short name=APAF-3
Cleaved into the following 2 chains:
    1- Recommended name:
            Caspase-9 subunit p35
    2- Recommended name:
            Caspase-9 subunit p10

Gene names

Name:	CASP9
Synonyms:	MCH6

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	416 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. Binding of caspase-9 to Apaf-1 leads to activation of the protease which then cleaves and activates caspase-3. Proteolytically cleaves poly(ADP-ribose) polymerase (PARP). Isoform 2 lacks activity is an dominant-negative inhibitor of caspase-9.
Catalytic activity	Strict requirement for an Asp residue at position P1 and with a marked preference for His at position P2. It has a preferred cleavage sequence of Leu-Gly-His-Asp-|-Xaa.
Subunit structure	Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 35 kDa (p35) and a 10 kDa (p10) subunit. Caspase-9 and APAF1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome C and ATP. Interacts with the inhibitors BIRC2, BIRC4, BIRC5 and BIRC7.
Tissue specificity	Ubiquitous, with highest expression in the heart, moderate expression in liver, skeletal muscle, and pancreas. Low levels in all other tissues.
Post-translational modification	Cleavages at Asp-315 by granzyme B and at Asp-330 by caspase-3 generate the two active subunits. Caspase-8 and -10 can also be involved in these processing events.
Sequence similarities	Belongs to the peptidase C14 family. Contains 1 CARD domain.

Ontologies

Keywords
Biological process	Apoptosis
Coding sequence diversity	Alternative splicing Polymorphism
Molecular function	Hydrolase Protease Thiol protease
PTM	Phosphoprotein Zymogen
Technical term	3D-structure
Gene Ontology (GO)
Biological process	caspase activation via cytochrome c Traceable author statement. Source: ProtInc proteolysis Inferred from electronic annotation. Source: InterPro
Cellular component	cytosol Inferred from Experiment. Source: Reactome
Molecular function	cysteine-type endopeptidase activity Ref.1 Traceable author statement. Source: ProtInc enzyme activator activity Traceable author statement. Source: ProtInc protein binding Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
APAF1	O14727	2	EBI-516799,EBI-446492
BIRC2	Q13490	1	EBI-516799,EBI-514538
BIRC4	P98170	4	EBI-516799,EBI-517127
BIRC5	O15392	1	EBI-516799,EBI-518823
BIRC7	Q96CA5	5	EBI-516799,EBI-517623
ILK	Q13418	1	EBI-516799,EBI-747644

Alternative products

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

Isoform 1 (identifier: P55211-1)

Also known as: 9L; Alpha;

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.

Isoform 2 (identifier: P55211-2)

Also known as: 9S; Beta;

The sequence of this isoform differs from the canonical sequence as follows:
     140-289: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Propeptide

1 – ?

Potential

PRO_0000004640

Chain

? – 315

Caspase-9 subunit p35

PRO_0000004641

Propeptide

316 – 330

15

PRO_0000004642

Chain

331 – 416

86

Caspase-9 subunit p10

PRO_0000004643

Regions

Domain

1 – 92

92

CARD

Sites

Active site

237

1

By similarity

Active site

287

1

By similarity

Amino acid modifications

Modified residue

125

1

Phosphothreonine

Modified residue

302

1

Phosphoserine

Modified residue

307

1

Phosphoserine

Modified residue

310

1

Phosphoserine

Natural variations

Alternative sequence

140 – 289

150

Missing in isoform 2.

VSP_000818

Natural variant

28

1

A → V: dbSNP rs1052571.

VAR_015415

Natural variant

99

1

S → L: dbSNP rs4646008.

VAR_015416

Natural variant

102

1

T → I: dbSNP rs2308941.

VAR_015417

Natural variant

106

1

L → V: dbSNP rs2308938.

VAR_015418

Natural variant

114

1

E → D: dbSNP rs2020897.

VAR_015419

Natural variant

173

1

R → H: dbSNP rs2308950.

VAR_015420

Natural variant

176

1

G → R: dbSNP rs2308949.

VAR_016131

Natural variant

185

1

I → M: dbSNP rs9282624.

VAR_022053

Natural variant

192

1

R → C: dbSNP rs2308939.

VAR_016132

Natural variant

221

1

Q → R: dbSNP rs1052576.

VAR_015421

Experimental info

Sequence conflict

32

1

R → S Ref.2 Ref.3 Ref.6

Sequence conflict

96

1

A → G in AAC50640. Ref.1

Sequence conflict

197

1

L → P Ref.2 Ref.3

Secondary structure

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416

Helix Strand Turn

Details...

Helix

3 – 11

9

Helix

13 – 19

7

Turn

23 – 25

3

Helix

26 – 31

6

Helix

37 – 44

8

Helix

51 – 62

12

Helix

69 – 78

10

Turn

79 – 81

3

Helix

83 – 94

12

Helix

143 – 147

5

Turn

149 – 151

3

Beta strand

161 – 167

7

Helix

173 – 175

3

Helix

183 – 196

14

Beta strand

199 – 206

8

Helix

209 – 221

13

Beta strand

228 – 239

12

Beta strand

244 – 246

3

Beta strand

249 – 251

3

Beta strand

257 – 259

3

Helix

260 – 265

6

Turn

269 – 271

3

Helix

273 – 275

3

Beta strand

280 – 287

8

Beta strand

340 – 346

7

Beta strand

351 – 353

3

Helix

362 – 374

13

Turn

375 – 377

3

Helix

380 – 392

13

Beta strand

408 – 410

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (9L) (Alpha) [UniParc]. Last modified February 22, 2003. Version 3. Checksum: 78E0180DF2A3BDD2	FASTA	416	46,281
	10 20 30 40 50 60 MDEADRRLLR RCRLRLVEEL QVDQLWDALL SRELFRPHMI EDIQRAGSGS RRDQARQLII 70 80 90 100 110 120 DLETRGSQAL PLFISCLEDT GQDMLASFLR TNRQAAKLSK PTLENLTPVV LRPEIRKPEV 130 140 150 160 170 180 LRPETPRPVD IGSGGFGDVG ALESLRGNAD LAYILSMEPC GHCLIINNVN FCRESGLRTR 190 200 210 220 230 240 TGSNIDCEKL RRRFSSLHFM VEVKGDLTAK KMVLALLELA QQDHGALDCC VVVILSHGCQ 250 260 270 280 290 300 ASHLQFPGAV YGTDGCPVSV EKIVNIFNGT SCPSLGGKPK LFFIQACGGE QKDHGFEVAS 310 320 330 340 350 360 TSPEDESPGS NPEPDATPFQ EGLRTFDQLD AISSLPTPSD IFVSYSTFPG FVSWRDPKSG 370 380 390 400 410 SWYVETLDDI FEQWAHSEDL QSLLLRVANA VSVKGIYKQM PGCFNFLRKK LFFKTS
	Isoform 2 (9S) (Beta) [UniParc]. Checksum: A12848BEBDC35A64		266	30,184
	10 20 30 40 50 60 MDEADRRLLR RCRLRLVEEL QVDQLWDALL SRELFRPHMI EDIQRAGSGS RRDQARQLII 70 80 90 100 110 120 DLETRGSQAL PLFISCLEDT GQDMLASFLR TNRQAAKLSK PTLENLTPVV LRPEIRKPEV 130 140 150 160 170 180 LRPETPRPVD IGSGGFGDVE QKDHGFEVAS TSPEDESPGS NPEPDATPFQ EGLRTFDQLD 190 200 210 220 230 240 AISSLPTPSD IFVSYSTFPG FVSWRDPKSG SWYVETLDDI FEQWAHSEDL QSLLLRVANA 250 260 VSVKGIYKQM PGCFNFLRKK LFFKTS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"ICE-LAP6, a novel member of the ICE/Ced-3 gene family, is activated by the cytotoxic T cell protease granzyme B." Duan H., Orth K., Chinnaiyan A.M., Poirier G.G., Froelich C.J., He W.-W., Dixit V.M. J. Biol. Chem. 271:16720-16724(1996) [PubMed: 8663294] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS VAL-28 AND ARG-221.
[2]	"The Ced-3/interleukin 1beta converting enzyme-like homolog Mch6 and the lamin-cleaving enzyme Mch2alpha are substrates for the apoptotic mediator CPP32." Srinivasula S.M., Fernandes-Alnemri T., Zangrilli J., Robertson N., Armstrong R.C., Wang L., Trapani J.A., Tomaselli K.J., Litwack G., Alnemri E.S. J. Biol. Chem. 271:27099-27106(1996) [PubMed: 8900201] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEOLYTIC PROCESSING. Tissue: T-cell.
[3]	"Genomic organization of the human caspase-9 gene on chromosome 1p36.1-p36.3." Hadano S., Nasir J., Nichol K., Rasper D.M., Vaillancourt J.P., Sherer S.W., Beatty B.G., Ikeda J.E., Nicholson D.W., Hayden M.R. Mamm. Genome 10:757-760(1999) [PubMed: 10384055] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"Identification of an endogenous dominant-negative short isoform of caspase-9 that can regulate apoptosis." Srinivasula S.M., Ahmad M., Guo Y., Zhan Y., Lazebnik Y., Fernandes-Alnemri T., Alnemri E.S. Cancer Res. 59:999-1002(1999) [PubMed: 10070954] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
[5]	"Molecular cloning and sequencing of a cDNA predicting an alternative form of pro-caspase-9 from human castric cancer cell lines." Izawa M., Mori T., Ito H., Sairenji T. Submitted (JUN-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). Tissue: Stomach cancer.
[6]	"A novel splicing product of human caspase-9 lacking protease activity." Miho Y., Momoi T., Fujita E. Submitted (DEC-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
[7]	"A caspase-9 variant missing the catalytic site is an endogenous inhibitor of apoptosis." Seol D.W., Billiar T.R. J. Biol. Chem. 274:2072-2076(1999) [PubMed: 9890966] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), VARIANT VAL-28.
[8]	"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], VARIANTS VAL-28; LEU-99; ILE-102; VAL-106; ASP-114; HIS-173 AND ARG-221.
[9]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D.,