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Reviewed, UniProtKB/Swiss-Prot P55211 (CASP9_HUMAN)

Last modified November 25, 2008. Version 104. 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 · Alternative products · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended 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
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length416 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence 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 processApoptosis
   Coding sequence diversityAlternative splicing
Polymorphism
   Molecular functionHydrolase
Protease
Thiol protease
   PTMPhosphoprotein
Zymogen
   Technical term3D-structure

Gene Ontology (GO)

   Biological processcaspase activation via cytochrome c

Traceable author statement. Source: ProtInc

proteolysis

Inferred from electronic annotation. Source: InterPro

   Cellular componentcytosol

Inferred from Experiment. Source: Reactome

   Molecular functioncysteine-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...

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 keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Propeptide1 – ? PotentialPRO_0000004640
Chain? – 315Caspase-9 subunit p35PRO_0000004641
Propeptide316 – 33015
PRO_0000004642
Chain331 – 41686Caspase-9 subunit p10
PRO_0000004643

Regions

Domain1 – 9292CARD

Sites

Active site2371 By similarity
Active site2871 By similarity

Amino acid modifications

Modified residue1251Phosphothreonine
Modified residue3021Phosphoserine
Modified residue3071Phosphoserine
Modified residue3101Phosphoserine

Natural variations

Alternative sequence140 – 289150Missing in isoform 2.
VSP_000818
Natural variant281A → V: dbSNP rs1052571.
VAR_015415
Natural variant991S → L: dbSNP rs4646008.
VAR_015416
Natural variant1021T → I: dbSNP rs2308941.
VAR_015417
Natural variant1061L → V: dbSNP rs2308938.
VAR_015418
Natural variant1141E → D: dbSNP rs2020897.
VAR_015419
Natural variant1731R → H: dbSNP rs2308950.
VAR_015420
Natural variant1761G → R: dbSNP rs2308949.
VAR_016131
Natural variant1851I → M: dbSNP rs9282624.
VAR_022053
Natural variant1921R → C: dbSNP rs2308939.
VAR_016132
Natural variant2211Q → R: dbSNP rs1052576.
VAR_015421

Experimental info

Sequence conflict321R → S Ref.2 Ref.3 Ref.6
Sequence conflict961A → G in AAC50640. Ref.1
Sequence conflict1971L → P Ref.2 Ref.3

Secondary structure

......................................................... 416
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (9L) (Alpha) [UniParc].

Last modified February 22, 2003. Version 3.
Checksum: 78E0180DF2A3BDD2

FASTA41646,281
        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 

« Hide

Isoform 2 (9S) (Beta) [UniParc].

Checksum: A12848BEBDC35A64
Show »

26630,184

References

« Hide '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. expand/collapse author list , 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.,