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Protein

Caspase-9

Gene

CASP9

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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. Promotes DNA damage-induced apoptosis in a ABL1/c-Abl-dependent manner. Proteolytically cleaves poly(ADP-ribose) polymerase (PARP).
Isoform 2 lacks activity is an dominant-negative inhibitor of caspase-9.

Catalytic activityi

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.1 Publication

Enzyme regulationi

Inhibited by the effector protein NleF that is produced by pathogenic E.coli; this inhibits apoptosis.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei237By similarity1
Active sitei287By similarity1

GO - Molecular functioni

  • cysteine-type endopeptidase activity Source: ProtInc
  • cysteine-type endopeptidase activity involved in execution phase of apoptosis Source: GO_Central
  • enzyme activator activity Source: ProtInc
  • peptidase activity Source: BHF-UCL
  • protein kinase binding Source: UniProtKB
  • SH3 domain binding Source: UniProtKB

GO - Biological processi

Keywordsi

Molecular functionHydrolase, Protease, Thiol protease
Biological processApoptosis

Enzyme and pathway databases

BRENDAi3.4.22.62. 2681.
ReactomeiR-HSA-111458. Formation of apoptosome.
R-HSA-111459. Activation of caspases through apoptosome-mediated cleavage.
R-HSA-111463. SMAC binds to IAPs.
R-HSA-111464. SMAC-mediated dissociation of IAP:caspase complexes.
R-HSA-168638. NOD1/2 Signaling Pathway.
R-HSA-198323. AKT phosphorylates targets in the cytosol.
R-HSA-418889. Ligand-independent caspase activation via DCC.
R-HSA-5674400. Constitutive Signaling by AKT1 E17K in Cancer.
SABIO-RKiP55211.
SIGNORiP55211.

Protein family/group databases

MEROPSiC14.010.

Names & Taxonomyi

Protein namesi
Recommended name:
Caspase-9 (EC:3.4.22.621 Publication)
Short name:
CASP-9
Alternative name(s):
Apoptotic protease Mch-6
Apoptotic protease-activating factor 3
Short name:
APAF-3
ICE-like apoptotic protease 6
Short name:
ICE-LAP6
Cleaved into the following 2 chains:
Gene namesi
Name:CASP9
Synonyms:MCH6
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

HGNCiHGNC:1511. CASP9.

Subcellular locationi

GO - Cellular componenti

  • apoptosome Source: UniProtKB
  • cytosol Source: UniProtKB
  • mitochondrion Source: Ensembl
  • nucleus Source: Ensembl

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi153Y → F: Inhibits tyrosine phosphorylation. Reduces caspase-9 subunit p35 formation in response to genotoxic stress. Attenuates ABL1/c-Abl-mediated caspase-3 activation, DNA fragmentation and UV irradiation-induced apoptosis. 1 Publication1

Organism-specific databases

DisGeNETi842.
OpenTargetsiENSG00000132906.
PharmGKBiPA26094.

Chemistry databases

ChEMBLiCHEMBL2273.
GuidetoPHARMACOLOGYi1625.

Polymorphism and mutation databases

DMDMi28558771.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_0000004641? – 315Caspase-9 subunit p35
PropeptideiPRO_00000046401 – ?Sequence analysis
PropeptideiPRO_0000004642316 – 330Add BLAST15
ChainiPRO_0000004643331 – 416Caspase-9 subunit p10Add BLAST86

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei125Phosphothreonine; by MAPK1Combined sources1 Publication1
Modified residuei153Phosphotyrosine; by ABL11 Publication1
Modified residuei302PhosphoserineCombined sources1
Modified residuei307PhosphoserineCombined sources1
Modified residuei310PhosphoserineCombined sources1

Post-translational modificationi

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.
Phosphorylated at Thr-125 by MAPK1/ERK2. Phosphorylation at Thr-125 is sufficient to block caspase-9 processing and subsequent caspase-3 activation. Phosphorylation on Tyr-153 by ABL1/c-Abl; occurs in the response of cells to DNA damage.2 Publications

Keywords - PTMi

Phosphoprotein, Zymogen

Proteomic databases

EPDiP55211.
MaxQBiP55211.
PaxDbiP55211.
PeptideAtlasiP55211.
PRIDEiP55211.

PTM databases

iPTMnetiP55211.
PhosphoSitePlusiP55211.

Miscellaneous databases

PMAP-CutDBiP55211.

Expressioni

Tissue specificityi

Ubiquitous, with highest expression in the heart, moderate expression in liver, skeletal muscle, and pancreas. Low levels in all other tissues. Within the heart, specifically expressed in myocytes.1 Publication

Developmental stagei

Expressed at low levels in fetal heart, at moderate levels in neonate heart, and at high levels in adult heart.1 Publication

Gene expression databases

BgeeiENSG00000132906.
CleanExiHS_CASP9.
ExpressionAtlasiP55211. baseline and differential.
GenevisibleiP55211. HS.

Organism-specific databases

HPAiCAB004348.
HPA001473.
HPA046488.

Interactioni

Subunit structurei

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 (inactive form) with EFHD2. Interacts with HAX1. Interacts with BIRC2/c-IAP1, XIAP/BIRC4, BIRC5/survivin, BIRC6/bruce and BIRC7/livin. Interacts with ABL1 (via SH3 domain); the interaction is direct and increases in the response of cells to genotoxic stress and ABL1/c-Abl activation. Interacts with NleF from pathogenic E.coli.7 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • protein kinase binding Source: UniProtKB
  • SH3 domain binding Source: UniProtKB

Protein-protein interaction databases

BioGridi107292. 34 interactors.
DIPiDIP-27625N.
IntActiP55211. 16 interactors.
MINTiMINT-89165.
STRINGi9606.ENSP00000330237.

Chemistry databases

BindingDBiP55211.

Structurei

Secondary structure

1416
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi3 – 11Combined sources9
Helixi13 – 19Combined sources7
Turni23 – 25Combined sources3
Helixi26 – 31Combined sources6
Helixi37 – 44Combined sources8
Helixi51 – 62Combined sources12
Helixi69 – 79Combined sources11
Helixi83 – 93Combined sources11
Helixi143 – 147Combined sources5
Turni149 – 151Combined sources3
Beta strandi157 – 159Combined sources3
Beta strandi161 – 167Combined sources7
Helixi173 – 175Combined sources3
Helixi183 – 196Combined sources14
Beta strandi199 – 206Combined sources8
Helixi209 – 221Combined sources13
Helixi224 – 226Combined sources3
Beta strandi228 – 239Combined sources12
Beta strandi244 – 246Combined sources3
Beta strandi249 – 251Combined sources3
Beta strandi257 – 259Combined sources3
Helixi260 – 265Combined sources6
Turni269 – 271Combined sources3
Helixi273 – 275Combined sources3
Beta strandi280 – 287Combined sources8
Beta strandi317 – 319Combined sources3
Beta strandi340 – 346Combined sources7
Beta strandi351 – 353Combined sources3
Beta strandi354 – 356Combined sources3
Turni357 – 359Combined sources3
Helixi362 – 374Combined sources13
Turni375 – 377Combined sources3
Helixi380 – 392Combined sources13
Beta strandi395 – 398Combined sources4
Beta strandi402 – 406Combined sources5
Beta strandi408 – 410Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1JXQX-ray2.80A/B/C/D140-416[»]
1NW9X-ray2.40B140-416[»]
2AR9X-ray2.80A/B/C/D139-416[»]
3D9TX-ray1.50C/D316-321[»]
3V3KX-ray3.49A/C/E/G/I/K/M/O141-416[»]
3YGSX-ray2.50P1-95[»]
4RHWX-ray2.10E/F1-100[»]
5JUYelectron microscopy4.10O/P/Q/R1-95[»]
5WVEelectron microscopy4.40S/T/U/V/Y1-100[»]
ProteinModelPortaliP55211.
SMRiP55211.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP55211.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini1 – 92CARDPROSITE-ProRule annotationAdd BLAST92

Sequence similaritiesi

Belongs to the peptidase C14A family.Curated

Phylogenomic databases

eggNOGiKOG3573. Eukaryota.
ENOG410ZQIE. LUCA.
GeneTreeiENSGT00760000118912.
HOVERGENiHBG059022.
InParanoidiP55211.
KOiK04399.
PhylomeDBiP55211.
TreeFamiTF102023.

Family and domain databases

CDDicd00032. CASc. 1 hit.
InterProiView protein in InterPro
IPR001315. CARD.
IPR033171. Caspase-9.
IPR029030. Caspase-like_dom.
IPR033139. Caspase_cys_AS.
IPR016129. Caspase_his_AS.
IPR011029. DEATH-like_dom.
IPR002138. Pept_C14_p10.
IPR001309. Pept_C14_p20.
IPR015917. Pept_C14A.
PANTHERiPTHR10454:SF173. PTHR10454:SF173. 1 hit.
PfamiView protein in Pfam
PF00619. CARD. 1 hit.
PRINTSiPR00376. IL1BCENZYME.
SMARTiView protein in SMART
SM00114. CARD. 1 hit.
SM00115. CASc. 1 hit.
SUPFAMiSSF47986. SSF47986. 1 hit.
SSF52129. SSF52129. 1 hit.
PROSITEiView protein in 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.

Sequences (4)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P55211-1) [UniParc]FASTAAdd to basket
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.

« Hide

        10         20         30         40         50
MDEADRRLLR RCRLRLVEEL QVDQLWDALL SRELFRPHMI EDIQRAGSGS
60 70 80 90 100
RRDQARQLII DLETRGSQAL PLFISCLEDT GQDMLASFLR TNRQAAKLSK
110 120 130 140 150
PTLENLTPVV LRPEIRKPEV LRPETPRPVD IGSGGFGDVG ALESLRGNAD
160 170 180 190 200
LAYILSMEPC GHCLIINNVN FCRESGLRTR TGSNIDCEKL RRRFSSLHFM
210 220 230 240 250
VEVKGDLTAK KMVLALLELA QQDHGALDCC VVVILSHGCQ ASHLQFPGAV
260 270 280 290 300
YGTDGCPVSV EKIVNIFNGT SCPSLGGKPK LFFIQACGGE QKDHGFEVAS
310 320 330 340 350
TSPEDESPGS NPEPDATPFQ EGLRTFDQLD AISSLPTPSD IFVSYSTFPG
360 370 380 390 400
FVSWRDPKSG SWYVETLDDI FEQWAHSEDL QSLLLRVANA VSVKGIYKQM
410
PGCFNFLRKK LFFKTS
Length:416
Mass (Da):46,281
Last modified:February 22, 2003 - v3
Checksum:i78E0180DF2A3BDD2
GO
Isoform 2 (identifier: P55211-2) [UniParc]FASTAAdd to basket
Also known as: 9S, Beta

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

Show »
Length:266
Mass (Da):30,184
Checksum:iA12848BEBDC35A64
GO
Isoform 3 (identifier: P55211-3) [UniParc]FASTAAdd to basket
Also known as: Gamma

The sequence of this isoform differs from the canonical sequence as follows:
     152-154: AYI → TVL
     155-416: Missing.

Note: May function as an endogenous apoptotic inhibitor, inhibits the BAX-mediated cleavage of procaspase-3.
Show »
Length:154
Mass (Da):17,397
Checksum:iB23A46C92AC6AA11
GO
Isoform 4 (identifier: P55211-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-83: Missing.

Show »
Length:333
Mass (Da):36,564
Checksum:i2B62F8CFD1FF3145
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti32R → S in AAC50776 (PubMed:8900201).Curated1
Sequence conflicti32R → S in BAA82697 (PubMed:10384055).Curated1
Sequence conflicti32R → S in BAA87905 (Ref. 6) Curated1
Sequence conflicti96A → G in AAC50640 (PubMed:8663294).Curated1
Sequence conflicti197L → P in AAC50776 (PubMed:8900201).Curated1
Sequence conflicti197L → P in BAA82697 (PubMed:10384055).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_01541528A → V4 PublicationsCorresponds to variant dbSNP:rs1052571Ensembl.1
Natural variantiVAR_01541699S → L1 PublicationCorresponds to variant dbSNP:rs4646008Ensembl.1
Natural variantiVAR_015417102T → I1 PublicationCorresponds to variant dbSNP:rs2308941Ensembl.1
Natural variantiVAR_015418106L → V1 PublicationCorresponds to variant dbSNP:rs2308938Ensembl.1
Natural variantiVAR_015419114E → D1 PublicationCorresponds to variant dbSNP:rs2020897Ensembl.1
Natural variantiVAR_059198136F → L. Corresponds to variant dbSNP:rs1820204Ensembl.1
Natural variantiVAR_015420173R → H1 PublicationCorresponds to variant dbSNP:rs2308950Ensembl.1
Natural variantiVAR_016131176G → R. Corresponds to variant dbSNP:rs2308949Ensembl.1
Natural variantiVAR_022053185I → M. Corresponds to variant dbSNP:rs9282624Ensembl.1
Natural variantiVAR_016132192R → C. Corresponds to variant dbSNP:rs2308939Ensembl.1
Natural variantiVAR_015421221Q → R2 PublicationsCorresponds to variant dbSNP:rs1052576Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0442561 – 83Missing in isoform 4. 1 PublicationAdd BLAST83
Alternative sequenceiVSP_000818140 – 289Missing in isoform 2. 4 PublicationsAdd BLAST150
Alternative sequenceiVSP_043910152 – 154AYI → TVL in isoform 3. 1 Publication3
Alternative sequenceiVSP_043911155 – 416Missing in isoform 3. 1 PublicationAdd BLAST262

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U56390 mRNA. Translation: AAC50640.1.
U60521 mRNA. Translation: AAC50776.1.
AB019205 Genomic DNA. Translation: BAA82697.1.
AF093130 mRNA. Translation: AAD12248.1.
AB015653 mRNA. Translation: BAA78780.1.
AB020979 mRNA. Translation: BAA87905.1.
AF110376 mRNA. Translation: AAD13615.1.
AY732490 mRNA. Translation: AAV33129.1.
AY214168 Genomic DNA. Translation: AAO21133.1.
BT006911 mRNA. Translation: AAP35557.1.
AK303743 mRNA. Translation: BAG64715.1.
AL512883 Genomic DNA. Translation: CAC42423.1.
AL512883 Genomic DNA. Translation: CAI12973.1.
CH471167 Genomic DNA. Translation: EAW51730.1.
CH471167 Genomic DNA. Translation: EAW51731.1.
BC002452 mRNA. Translation: AAH02452.1.
BC006463 mRNA. Translation: AAH06463.1.
CCDSiCCDS158.1. [P55211-1]
CCDS159.2. [P55211-4]
CCDS59995.1. [P55211-2]
PIRiG02635.
RefSeqiNP_001220.2. NM_001229.4. [P55211-1]
NP_001264983.1. NM_001278054.1. [P55211-2]
NP_127463.2. NM_032996.3. [P55211-4]
XP_005246071.1. XM_005246014.2. [P55211-4]
UniGeneiHs.329502.

Genome annotation databases

EnsembliENST00000333868; ENSP00000330237; ENSG00000132906. [P55211-1]
ENST00000348549; ENSP00000255256; ENSG00000132906. [P55211-2]
ENST00000375890; ENSP00000365051; ENSG00000132906. [P55211-4]
GeneIDi842.
KEGGihsa:842.
UCSCiuc001awn.5. human. [P55211-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

Entry informationi

Entry nameiCASP9_HUMAN
AccessioniPrimary (citable) accession number: P55211
Secondary accession number(s): B4E1A3
, O95348, Q53Y70, Q5JRU9, Q5UGI1, Q92852, Q9BQ62, Q9UEQ3, Q9UIJ8
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: February 22, 2003
Last modified: June 7, 2017
This is version 195 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Peptidase families
    Classification of peptidase families and list of entries
  7. SIMILARITY comments
    Index of protein domains and families