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]
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] Caspase-9 has multiple additional cellular functions that are independent of its role in apoptosis. Nonapoptotic roles of caspase-9 include regulation of necroptosis, cellular differentiation, innate immune response, sensory neuron maturation, mitochondrial homeostasis, corticospinal circuit organization, and ischemic vascular injury. [9] Without correct function, abnormal tissue development can occur leading to abnormal function, diseases and premature death. [8] Caspase-9 loss-of-function mutations have been associated with immunodeficiency/lymphoproliferation, neural tube defects, and Li-Fraumeni-like syndrome. Increased caspase-9 activity is implicated in the progression of amyotrophic lateral sclerosis, retinal detachment, and slow-channel syndrome, as well as various other neurological, autoimmune, and cardiovascular disorders. [9]
Different protein isoforms of caspase-9 are produced due to alternative splicing.[10]
Structure
editSimilar 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.[11] The pro-domain is linked to the catalytic domain by a linker loop.[12]
The caspase-9 monomer consists of one large and one small subunit, both comprising the catalytic domain.[13] Differing from the normally conserved active site motif QACRG in other caspases, caspase-9 has the motif QACGG.[14][12]
When dimerized, caspase-9 has two different active site conformations within each dimer.[13] 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.[13] Surface loops around the active site are short, giving rise to broad substrate specificity as the substrate-binding cleft is more open.[15] 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.[16]
Localization
editWithin the cell, caspase-9 in humans is found in the mitochondria, cytosol, and nucleus.[17]
Protein expression
editCaspase-9 in humans is expressed in fetus and adult tissues.[14][12] 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.[18] The liver, pancreas, and skeletal muscle express this enzyme at a moderate level, and all other tissues express caspase-9 at low levels.[18]
Mechanism
editActive caspase-9 works as an initiating caspase by cleaving, thus activating downstream executioner caspases, initiating apoptosis.[19] 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.[13][20] It is then recruited and activated by the CARDs in apaf-1, recognizing the CARDs in caspase-9.[21]
Processing
editBefore activation can occur, caspase-9 has to be processed.[22] Initially, caspase-9 is made as an inactive single-chain zymogen.[22] Processing occurs when the apoptosome binds to pro-caspase-9 as apaf-1 assists in the autoproteolytic processing of the zymogen.[22] The processed caspase-9 stays bound to the apoptosome complex, forming a holoenzyme.[23]
Activation
editActivation occurs when caspase-9 dimerizes, and there are two different ways for which this can occur:
- Caspase-9 is auto-activated when it binds to apaf-1(apoptosome), as apaf-1 oligomerizes the precursor molecules of pro-caspase-9.[17]
- Previously activated caspases can cleave caspase-9, causing its dimerization.[24]
Catalytic activity
editCaspase-9 has a preferred cleavage sequence of Leu-Gly-His-Asp-(cut)-X.[16]
Regulation
editNegative 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.[25] Akt acts as an allosteric inhibitor of caspase-9 because the site of phosphorylation of serine-196 is far from the catalytic site.[25] The inhibitor affects the dimerization of caspase-9 and causes a conformational change that affects the substrate-binding cleft of caspase-9.[25]
Akt can act on both processed and unprocessed caspase-9 in-vitro, where phosphorylation on processed caspase-9 occurs on the large subunit.[26]
Deficiencies and mutations
editA deficiency in caspase-9 largely affects the brain and its development.[27] The effects of having a mutation or deficiency in this caspase compared to others is detrimental.[27] 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.[28] 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.[28] Low amounts of caspase-9 leads to cancer and neurodegenerative diseases like Alzheimer's disease.[28] 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.[29] 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.[30]
Clinical significance
editThe 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.[19] In the context of graft versus host disease, caspase-9 can be introduced as an inducible switch.[31] In the presence of a small molecule, it will dimerize and trigger apoptosis, eliminating lymphocytes.[31]
iCasp9
editiCasp9 (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.[32] 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.[32] iCasp9 can be added to the CAR T cells as an inducible suicide gene.[33]
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.[33] This, in turn, induces expression of caspase-9, which triggers cell death of the CAR T cells.[33]
Alternative transcripts
editThrough alternative splicing, four difference caspase-9 variants are produced.
Caspase-9α (9L)
editThis variant is used as the reference sequence, and it has full cysteine protease activity.[11][34]
Caspase-9β (9S)
editIsoform 2 doesn't include exons 3, 4, 5, and 6; it is missing amino acids 140-289.[11][34] 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.[11][35] Caspase-9β is referred to as the endogenous dominant-negative isoform.
Caspase-9γ
editThis variant is missing amino acids 155-416, and for amino acids 152-154, the sequence AYI is changed to TVL.[34]
Isoform 4
editIn comparison with the reference sequence, it is missing amino acids 1-83.[34]
Interactions
editCaspase-9 has been shown to interact with:
See also
editReferences
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Further reading
edit- 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. doi:10.1016/s1016-8478(23)12897-4. PMID 16511342.
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- 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. doi:10.1016/S0021-9258(18)47344-9. 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. Bibcode:1996PNAS...9314486S. doi:10.1073/pnas.93.25.14486. PMC 26159. PMID 8962078.
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- 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. Bibcode:1998PNAS...95.4386H. doi:10.1073/pnas.95.8.4386. PMC 22498. PMID 9539746.
- Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, Alnemri ES, Salvesen GS, Reed JC (April 1998). "IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases". The EMBO Journal. 17 (8): 2215–23. doi:10.1093/emboj/17.8.2215. PMC 1170566. PMID 9545235.
- Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Alnemri ES (June 1998). "Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization". Molecular Cell. 1 (7): 949–57. doi:10.1016/S1097-2765(00)80095-7. PMID 9651578.
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External links
edit- The MEROPS online database for peptidases and their inhibitors: C14.010[permanent dead link ]