Caspase-9

Caspase-9 is an enzyme that in humans is encoded by the CASP9 gene. It is an initiator caspase,[5] critical to the apoptotic pathway found in many tissues.[6] Caspase-9 homologs have been identified in all mammals for which they are known to exist, such as Mus musculus and Pan troglodytes.[7]

CASP9
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4RHW, 1JXQ, 1NW9, 2AR9, 3D9T, 3V3K, 3YGS
Identifiers
Aliases	CASP9, APAF-3, APAF3, ICE-LAP6, MCH6, PPP1R56, caspase 9
External IDs	OMIM: 602234 MGI: 1277950 HomoloGene: 31024 GeneCards: CASP9
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1p36.21 Start 15,490,832 bp[1] End 15,526,534 bp[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)[2] Band 4|4 E1 Start 141,793,612 bp[2] End 141,815,976 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • cysteine-type peptidase activity • SH3 domain binding • peptidase activity • GO:0001948 protein binding • GO:0010577 enzyme activator activity • hydrolase activity • protein kinase binding • cysteine-type endopeptidase activity involved in execution phase of apoptosis • cysteine-type endopeptidase activity • identical protein binding • cysteine-type endopeptidase activity involved in apoptotic signaling pathway • cysteine-type endopeptidase activity involved in apoptotic process Cellular component • cytoplasm • cytosol • mitochondrion • apoptosome • cell nucleus • macromolecular complex Biological process • regulation of apoptotic process • response to estradiol • response to organic cyclic compound • signal transduction in response to DNA damage • cellular response to UV • response to antibiotic • cellular response to organic cyclic compound • aging • platelet formation • glial cell apoptotic process • cellular response to dexamethasone stimulus • proteolysis • cellular response to DNA damage stimulus • response to lipopolysaccharide • positive regulation of neuron apoptotic process • activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c • intrinsic apoptotic signaling pathway in response to DNA damage • extrinsic apoptotic signaling pathway in absence of ligand • regulation of response to DNA damage stimulus • response to cobalt ion • activation of cysteine-type endopeptidase activity involved in apoptotic process • response to UV • execution phase of apoptosis • positive regulation of apoptotic process • apoptotic process • kidney development • response to ischemia • leukocyte apoptotic process Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	842	12371
Ensembl	ENSG00000132906	ENSMUSG00000028914
UniProt	P55211	Q8C3Q9
RefSeq (mRNA)	NM_001229 NM_001278054 NM_032996	NM_001277932 NM_015733 NM_001355176
RefSeq (protein)	NP_001220 NP_001264983 NP_127463	NP_001264861 NP_056548 NP_001342105
Location (UCSC)	Chr 1: 15.49 – 15.53 Mb	Chr 4: 141.79 – 141.82 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Caspase-9 belongs to a family of caspases, cysteine-aspartic proteases involved in apoptosis and cytokine signalling.[8] Apoptotic signals cause the release of cytochrome c from mitochondria and activation of apaf-1 (apoptosome), which then cleaves the pro-enzyme of caspase-9 into the active dimer form.[6] Regulation of this enzyme occurs through phosphorylation by an allosteric inhibitor, inhibiting dimerization and inducing a conformational change.[8]

Correct caspase-9 function is required for apoptosis, leading to the normal development of the central nervous system.[8] Without correct function, abnormal tissue development can occur leading to abnormal function, diseases and premature death.[8] Certain diseases involving caspase-9 are treated with therapy by targeting this enzyme.[8]

Different protein isoforms of caspase-9 are produced due to alternative splicing.[9]

Structure

Similar to other caspases, caspase-9 has three domains: N-terminal pro-domain, large subunit, and a small subunit.[8] The N-terminal pro-domain is also called the long pro-domain and this contains the caspase activation domain (CARD) motif.[10] The pro-domain is linked to the catalytic domain by a linker loop.[11]

The caspase-9 monomer consists of one large and one small subunit, both comprising the catalytic domain.[12] Differing from the normally conserved active site motif QACRG in other caspases, caspase-9 has the motif QACGG.[13][11]

When dimerized, caspase-9 has two different active site conformations within each dimer.[12] One site closely resembles the catalytic site of other caspases, whereas the second has no 'activation loop', disrupting the catalytic machinery in that particular active site.[12] Surface loops around the active site are short, giving rise to broad substrate specificity as the substrate-binding cleft is more open.[14] Within caspase-9's active site, in order for catalytic activity to occur there has to be specific amino acids in the right position. Amino acid Asp at position P1 is essential, with a preference for amino acid His at position P2.[15]

Localization

Within the cell, caspase-9 in humans is found in the mitochondria, cytosol, and nucleus.[16]

Protein expression

Caspase-9 in humans is expressed in fetus and adult tissues.[13][11] Tissue expression of caspase-9 is ubiquitous with the highest expression in the brain and heart, specifically at the developmental stage of an adult in the heart's muscle cells.[17] The liver, pancreas, and skeletal muscle express this enzyme at a moderate level, and all other tissues express caspase-9 at low levels.[17]

Mechanism

Active caspase-9 works as an initiating caspase by cleaving, thus activating downstream executioner caspases, initiating apoptosis.[18] Once activated, caspase-9 goes on to cleave caspase-3, -6, and -7, initiating the caspase cascade as they cleave several other cellular targets.[8]

When caspase-9 is inactive, it exists in the cytosol as a zymogen, in its monomer form.[12][19] It is then recruited and activated by the CARDs in apaf-1, recognizing the CARDs in caspase-9.[20]

Processing

Before activation can occur, caspase-9 has to be processed.[21] Initially, caspase-9 is made as an inactive single-chain zymogen.[21] Processing occurs when the apoptosome binds to pro-caspase-9 as apaf-1 assists in the autoproteolytic processing of the zymogen.[21] The processed caspase-9 stays bound to the apoptosome complex, forming a holoenzyme.[22]

Activation

Activation occurs when caspase-9 dimerizes, and there are two different ways for which this can occur:

1. Caspase-9 is auto-activated when it binds to apaf-1(apoptosome), as apaf-1 oligomerizes the precursor molecules of pro-caspase-9.[16]
2. Previously activated caspases can cleave caspase-9, causing its dimerization.[23]

Catalytic activity

Caspase-9 has a preferred cleavage sequence of Leu-Gly-His-Asp-(cut)-X.[15]

Regulation

Negative regulation of caspase-9 occurs through phosphorylation.[8] This is done by a serine-threonine kinase, Akt, on serine-196 which inhibits the activation and protease activity of caspase-9, suppressing caspase-9 and further activation of apoptosis.[24] Akt acts as an allosteric inhibitor of caspase-9 because the site of phosphorylation of serine-196 is far from the catalytic site.[24] The inhibitor affects the dimerization of caspase-9 and causes a conformational change that affects the substrate-binding cleft of caspase-9.[24]

Akt can act on both processed and unprocessed caspase-9 in-vitro, where phosphorylation on processed caspase-9 occurs on the large subunit.[25]

Deficiencies and mutations

A deficiency in caspase-9 largely affects the brain and its development.[26] The effects of having a mutation or deficiency in this caspase compared to others is detrimental.[26] The initiating role caspase-9 plays in apoptosis is the cause for the severe effects seen in those with an atypical caspase-9.

Mice with insufficient caspase-9 have a main phenotype of an affected or abnormal brain.[8] Larger brains due to a decrease in apoptosis, resulting in an increase of extra neurons is an example of a phenotype seen in caspase-9 deficient mice.[27] Those homozygous for no caspase-9 die perinatally as a result of an abnormally developed cerebrum.[8]

In humans, expression of caspase-9 varies from tissue to tissue, and the different levels have a physiological role.[27] Low amounts of caspase-9 leads to cancer and neurodegenerative diseases like Alzheimer's disease.[27] Further alterations at single-nucleotide polymorphism (SNP) levels and whole gene levels of caspase-9 can cause germ-line mutations linked to non-Hodgkin's lymphoma.[28] Certain polymorphisms in the promoter of caspase-9 enhances the rate at which caspase-9 is expressed, and this can increase a person's risk of lung cancer.[29]

Clinical significance

The effects of abnormal caspase-9 levels or function impacts the clinical world. The impact caspase-9 has on the brain can lead to future work in inhibition through targeted therapy, specifically with diseases associated with the brain as this enzyme may take part in the developmental pathways of neuronal disorders.[8]

The introduction of caspases may also have medical benefits.[18] In the context of graft versus host disease, caspase-9 can be introduced as an inducible switch.[30] In the presence of a small molecule, it will dimerize and trigger apoptosis, eliminating lymphocytes.[30]

iCasp9

iCasp9 (inducible caspase-9) is a type of control system for chimeric antigen receptor T cells (CAR T cells). CAR T cells are genetically modified T cells that exhibit cytotoxicity to tumor cells. Evidence shows that CAR T cells are effective in treating B-cell malignancies. However, as CAR T cells introduce toxicity, user control of the cells and their targets is critical.[31] One of the various ways to exert control over CAR T cell is through drug-controlled synthetic systems. iCasp9 was created by modifying caspase-9 and fusing it with the FK506 binding protein.[31] iCasp9 can be added to the CAR T cells as an inducible suicide gene.[32]

If therapy with CAR T cells results in severe side effects, iCasp9 can be used to halt treatment. Administering a small-molecule drug such as rapamycin causes the drug to bind to the FK506 domain.[32] This, in turn, induces expression of caspase-9, which triggers cell death of the CAR T cells.[32]

Alternative transcripts

Through alternative splicing, four difference caspase-9 variants are produced.

Caspase-9α (9L)

This variant is used as the reference sequence, and it has full cysteine protease activity.[10][33]

Caspase-9β (9S)

Isoform 2 doesn't include exons 3, 4, 5, and 6; it is missing amino acids 140-289.[10][33] Caspase-9S doesn't have central catalytic domain, therefore it functions as an inhibitor of caspase-9α by attaching to the apoptosome, suppressing the caspase enzyme cascade and apoptosis.[10][34] Caspase-9β is referred to as the endogenous dominant-negative isoform.

Caspase-9γ

This variant is missing amino acids 155-416, and for amino acids 152-154, the sequence AYI is changed to TVL.[33]

Isoform 4

In comparison with the reference sequence, it is missing amino acids 1-83.[33]

Interactions

Caspase-9 has been shown to interact with:

• APAF1[35][36][6][37][38]
• BIRC2,[39]
• Baculoviral IAP repeat-containing protein 3,[39]
• Caspase 8,[40][41]
• NLRP1,[35][42] and
• XIAP.[39][43][44][45]

Overview of signal transduction pathways involved in apoptosis.

See also

• The Proteolysis Map
• Caspase
• Caspase-3
• Apoptosome
• Apaf-1

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Further reading

• Cohen GM (August 1997). "Caspases: the executioners of apoptosis". The Biochemical Journal. 326 (Pt 1): 1–16. doi:10.1042/bj3260001. PMC 1218630. PMID 9337844.
• Deveraux QL, Reed JC (February 1999). "IAP family proteins--suppressors of apoptosis". Genes & Development. 13 (3): 239–52. doi:10.1101/gad.13.3.239. PMID 9990849.
• Zhao LJ, Zhu H (December 2004). "Structure and function of HIV-1 auxiliary regulatory protein Vpr: novel clues to drug design". Current Drug Targets. Immune, Endocrine and Metabolic Disorders. 4 (4): 265–75. doi:10.2174/1568008043339668. PMID 15578977.
• Le Rouzic E, Benichou S (February 2005). "The Vpr protein from HIV-1: distinct roles along the viral life cycle". Retrovirology. 2: 11. doi:10.1186/1742-4690-2-11. PMC 554975. PMID 15725353.
• Moon HS, Yang JS (February 2006). "Role of HIV Vpr as a regulator of apoptosis and an effector on bystander cells". Molecules and Cells. 21 (1): 7–20. PMID 16511342.
• Kopp S (September 1976). "Reproducibility of response to a questionnaire on symptoms of masticatory dysfunction". Community Dentistry and Oral Epidemiology. 4 (5): 205–9. doi:10.1111/j.1600-0528.1976.tb00985.x. PMID 1067155.
• Fernandes-Alnemri T, Litwack G, Alnemri ES (December 1994). "CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme". The Journal of Biological Chemistry. 269 (49): 30761–4. PMID 7983002.
• Duan H, Orth K, Chinnaiyan AM, Poirier GG, Froelich CJ, He WW, Dixit VM (July 1996). "ICE-LAP6, a novel member of the ICE/Ced-3 gene family, is activated by the cytotoxic T cell protease granzyme B". The Journal of Biological Chemistry. 271 (28): 16720–4. doi:10.1074/jbc.271.28.16720. PMID 8663294.
• Srinivasula SM, Fernandes-Alnemri T, Zangrilli J, Robertson N, Armstrong RC, Wang L, Trapani JA, Tomaselli KJ, Litwack G, Alnemri ES (October 1996). "The Ced-3/interleukin 1beta converting enzyme-like homolog Mch6 and the lamin-cleaving enzyme Mch2alpha are substrates for the apoptotic mediator CPP32". The Journal of Biological Chemistry. 271 (43): 27099–106. doi:10.1074/jbc.271.43.27099. PMID 8900201.
• Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Litwack G, Alnemri ES (December 1996). "Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases". Proceedings of the National Academy of Sciences of the United States of America. 93 (25): 14486–91. doi:10.1073/pnas.93.25.14486. PMC 26159. PMID 8962078.
• Kothakota S, Azuma T, Reinhard C, Klippel A, Tang J, Chu K, McGarry TJ, Kirschner MW, Koths K, Kwiatkowski DJ, Williams LT (October 1997). "Caspase-3-generated fragment of gelsolin: effector of morphological change in apoptosis". Science. 278 (5336): 294–8. doi:10.1126/science.278.5336.294. PMID 9323209.
• Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (November 1997). "Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade". Cell. 91 (4): 479–89. doi:10.1016/S0092-8674(00)80434-1. PMID 9390557.
• Pan G, O'Rourke K, Dixit VM (March 1998). "Caspase-9, Bcl-XL, and Apaf-1 form a ternary complex". The Journal of Biological Chemistry. 273 (10): 5841–5. doi:10.1074/jbc.273.10.5841. PMID 9488720.
• Hu Y, Benedict MA, Wu D, Inohara N, Núñez G (April 1998). "Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation". Proceedings of the National Academy of Sciences of the United States of America. 95 (8): 4386–91. doi:10.1073/pnas.95.8.4386. PMC 22498. PMID 9539746.
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External links

• The MEROPS online database for peptidases and their inhibitors: C14.010