Caspase-2

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Caspase-2
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EC no. 3.4.22.55
CAS no. 182372-14-1
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Caspase-2 (EC 3.4.22.55, ICH-1, NEDD-2, caspase-2L, caspase-2S, neural precursor cell expressed developmentally down-regulated protein 2, CASP-2, NEDD2 protein) is an enzyme. [1] [2] [3] [4] [5] [6] This enzyme catalyses the following chemical reaction

Contents

Strict requirement for an Asp residue at P1, with Asp316 being essential for proteolytic activity and has a preferred cleavage sequence of Val-Asp-Val-Ala-Asp-

Caspase-2 is an initiator caspase, as are caspase-8 (EC 3.4.22.61), caspase-9 (EC 3.4.22.62) and caspase-10 (EC 3.4.22.63).

Caspase-2 is an important enzyme in the cysteine aspartate protease family, known as caspases, which are central to the regulation of apoptosis and, in certain cases, inflammation. While many caspases are mainly involved in the initiation and execution of cell death, caspase-2 has a broader range of functions. Beyond its apoptotic role, it contributes to maintaining genomic stability and responding to cellular stress, demonstrating its multifaceted role in cellular processes and its wider importance in cell regulation mechanisms. [7] When caspases are activated, they break down a variety of specific protein substrates, triggering the distinct features of apoptosis, such as DNA fragmentation, chromatin condensation, and plasma membrane blebbing. Caspase-2, known as the most evolutionarily conserved caspase, holds a unique role in both apoptotic and non-apoptotic functions. Its evolutionary stability highlights its essential contributions to cellular processes like preserving genomic integrity and regulating stress responses, demonstrating its broader significance beyond just apoptosis. [8]

Caspase-2 activation through dimerization.

Caspases are classified into two fundamental groups: initiator caspases, including caspase-8 and caspase-9, and executioner caspases, such as caspase-3 and caspase-7, each playing distinct roles in the apoptosis signaling pathway. [9] Initiator caspases serve as critical regulators at the top of various signaling cascades, orchestrating the activation of executioner caspases through both direct and indirect mechanisms. While these caspases are typically found as inactive monomers within the cell, their activation relies on dimerization. This dimerization occurs when initiator caspases are recruited to large protein complexes that function as intricate signaling platforms, enabling their conversion to an active form. [10] Caspases are produced as single-chain pro-caspases that undergo cleavage within their chains, resulting in the formation of large and small catalytic subunits. Although this cleavage is both necessary and sufficient for activating executioner caspases, evidence indicates that initiator caspases require dimerization for activation. Furthermore, the intra-chain cleavage that follows this process helps to stabilize the active form of the enzyme. [11] Caspase-2 is activated via a mechanism that parallels those of other caspases. In its monomeric state, it shows no measurable activity, regardless of its cleavage status. Conversely, a dimeric form of a cleavage-deficient mutant retains about 20% of its enzymatic activity. Following autoprocessing of the dimerized form, caspase-2 becomes fully active. [12] Consequently, the first step in the activation of caspase-2 is dimerization.

Related Research Articles

<span class="mw-page-title-main">Apoptosis</span> Type of programmed cell death in multicellular organisms

Apoptosis is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, and mRNA decay. The average adult human loses 50 to 70 billion cells each day due to apoptosis. For the average human child between 8 and 14 years old, each day the approximate loss is 20 to 30 billion cells.

<span class="mw-page-title-main">Caspase</span> Family of cysteine proteases

Caspases are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. As of 2009, there are 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions.

<span class="mw-page-title-main">Fas ligand</span> Protein-coding gene in the species Homo sapiens

Fas ligand is a type-II transmembrane protein expressed on various types of cells, including cytotoxic T lymphocytes, monocytes, neutrophils, breast epithelial cells, vascular endothelial cells and natural killer (NK) cells. It binds with its receptor, called FAS receptor and plays a crucial role in the regulation of the immune system and in induction of apoptosis, a programmed cell death.

<span class="mw-page-title-main">Caspase-9</span> Enzyme found in humans

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

Inhibitors of apoptosis are a group of proteins that mainly act on the intrinsic pathway that block programmed cell death, which can frequently lead to cancer or other effects for the cell if mutated or improperly regulated. Many of these inhibitors act to block caspases, a family of cysteine proteases that play an integral role in apoptosis. Some of these inhibitors include the Bcl-2 family, viral inhibitor crmA, and IAP's.

<span class="mw-page-title-main">Caspase 2</span> Enzyme found in humans

Caspase 2 also known as CASP2 is an enzyme that, in humans, is encoded by the CASP2 gene. CASP2 orthologs have been identified in nearly all mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts.

<span class="mw-page-title-main">Caspase 3</span> Protein found in humans

Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the CASP3 gene. CASP3 orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts.

<span class="mw-page-title-main">Caspase 7</span> Protein found in humans

Caspase-7, apoptosis-related cysteine peptidase, also known as CASP7, is a human protein encoded by the CASP7 gene. CASP7 orthologs have been identified in nearly all mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts.

<span class="mw-page-title-main">Caspase 6</span> Enzyme found in humans

Caspase-6 is an enzyme that in humans is encoded by the CASP6 gene. CASP6 orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts. Caspase-6 has known functions in apoptosis, early immune response and neurodegeneration in Huntington's and Alzheimer's disease.

<span class="mw-page-title-main">Caspase 10</span> Enzyme found in humans

Caspase-10 is an enzyme that, in humans, is encoded by the CASP10 gene.

<span class="mw-page-title-main">APAF1</span> Mammalian protein found in Homo sapiens

Apoptotic protease activating factor 1, also known as APAF1, is a human homolog of C. elegans CED-4 gene.

<span class="mw-page-title-main">STK3</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein kinase 3 is an enzyme that in humans is encoded by the STK3 gene.

<span class="mw-page-title-main">LRDD</span> Protein-coding gene in the species Homo sapiens

Leucine-rich repeats and death domain containing, also known as LRDD or p53-induced protein with a death domain (PIDD), is a protein which in humans is encoded by the LRDD gene.

<span class="mw-page-title-main">Caspase-activated DNase</span> Protein found in humans

Caspase-activated DNase (CAD) or DNA fragmentation factor subunit beta is a protein that in humans is encoded by the DFFB gene. It breaks up the DNA during apoptosis and promotes cell differentiation. It is usually an inactive monomer inhibited by ICAD. This is cleaved before dimerization.

<span class="mw-page-title-main">Bcl-2 family</span>

The Bcl-2 family consists of a number of evolutionarily-conserved proteins that share Bcl-2 homology (BH) domains. The Bcl-2 family is most notable for their regulation of apoptosis, a form of programmed cell death, at the mitochondrion. The Bcl-2 family proteins consists of members that either promote or inhibit apoptosis, and control apoptosis by governing mitochondrial outer membrane permeabilization (MOMP), which is a key step in the intrinsic pathway of apoptosis. A total of 25 genes in the Bcl-2 family were identified by 2008.

<span class="mw-page-title-main">Necroptosis</span> Programmed form of necrosis, or inflammatory cell death

Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via apoptosis. The discovery of necroptosis showed that cells can execute necrosis in a programmed fashion and that apoptosis is not always the preferred form of cell death. Furthermore, the immunogenic nature of necroptosis favors its participation in certain circumstances, such as aiding in defence against pathogens by the immune system. Necroptosis is well defined as a viral defense mechanism, allowing the cell to undergo "cellular suicide" in a caspase-independent fashion in the presence of viral caspase inhibitors to restrict virus replication. In addition to being a response to disease, necroptosis has also been characterized as a component of inflammatory diseases such as Crohn's disease, pancreatitis, and myocardial infarction.

Caspase-10 is an enzyme. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Early 35 kDa protein</span> Anti-apoptotic viral protein

The Early 35 kDa protein, or P35 in short, is a baculoviral protein that inhibits apoptosis in the cells infected by the virus. Although baculoviruses infect only invertebrates in nature, ectopic expression of P35 in vertebrate animals and cells also results in inhibition of apoptosis, thus indicating a universal mechanism. P35 has been shown to be a caspase inhibitor with a very wide spectrum of activity both in regard to inhibited caspase types and to species in which the mechanism is conserved.

Ced-3 is one of the major protein components of the programmed cell death (PCD) pathway for Caenorhabditis elegans. There are in total 14 genes that are involved in programmed cell death, other important ones including ced-4 and ced-9 genes. The healthy nematode worm will require 131 somatic cell deaths out of the 1090 cells during the developmental stages. The gene initially encodes for a prototypical caspase (procaspase) where the active cysteine residue cleaves aspartate residues, thus becoming a functional caspase. Ced-3 is an executioner caspase that must dimerize with itself and be initiated by ced-4 in order to become active. Once active, it will have a series of reactions that will ultimately lead to the apoptosis of targeted cells.

<span class="mw-page-title-main">Death regulator Nedd2-like caspase</span> Type of cysteine protease

Death regulator Nedd2-like caspase was firstly identified and characterised in Drosophila in 1999 as a cysteine protease containing an amino-terminal caspase recruitment domain. At first, it was thought of as an effector caspase involved in apoptosis, but subsequent findings have proved that it is, in fact, an initiator caspase with a crucial role in said type of programmed cell death.

References

  1. ↑ Kumar S, Kinoshita M, Noda M, Copeland NG, Jenkins NA (July 1994). "Induction of apoptosis by the mouse Nedd2 gene, which encodes a protein similar to the product of the Caenorhabditis elegans cell death gene ced-3 and the mammalian IL-1 beta-converting enzyme". Genes & Development. 8 (14): 1613–26. doi: 10.1101/gad.8.14.1613 . PMID   7958843.
  2. ↑ Wang L, Miura M, Bergeron L, Zhu H, Yuan J (September 1994). "Ich-1, an Ice/ced-3-related gene, encodes both positive and negative regulators of programmed cell death". Cell. 78 (5): 739–50. doi:10.1016/S0092-8674(94)90422-7. PMID   8087842.
  3. ↑ Li H, Bergeron L, Cryns V, Pasternack MS, Zhu H, Shi L, Greenberg A, Yuan J (August 1997). "Activation of caspase-2 in apoptosis". The Journal of Biological Chemistry. 272 (34): 21010–7. doi: 10.1074/jbc.272.34.21010 . PMID   9261102.
  4. ↑ Mancini M, Machamer CE, Roy S, Nicholson DW, Thornberry NA, Casciola-Rosen LA, Rosen A (May 2000). "Caspase-2 is localized at the Golgi complex and cleaves golgin-160 during apoptosis". The Journal of Cell Biology. 149 (3): 603–12. doi:10.1083/jcb.149.3.603. PMC   2174848 . PMID   10791974.
  5. ↑ Zhivotovsky B, Orrenius S (June 2005). "Caspase-2 function in response to DNA damage". Biochemical and Biophysical Research Communications. 331 (3): 859–67. doi: 10.1016/j.bbrc.2005.03.191 . PMID   15865942.
  6. ↑ Chang HY, Yang X (December 2000). "Proteases for cell suicide: functions and regulation of caspases". Microbiology and Molecular Biology Reviews. 64 (4): 821–46. doi:10.1128/mmbr.64.4.821-846.2000. PMC   99015 . PMID   11104820.
  7. ↑ Creagh, Emma M.; Conroy, Helen; Martin, Seamus J. (2003-05-12). "Caspase-activation pathways in apoptosis and immunity". Immunological Reviews. 193 (1): 10–21. doi:10.1034/j.1600-065x.2003.00048.x. ISSN   0105-2896. PMID   12752666.
  8. ↑ Krumschnabel, G.; Sohm, B.; Bock, F.; Manzl, C.; Villunger, A. (21 November 2008). "The enigma of caspase-2: the laymen's view". Cell Death & Differentiation. 16 (2): 195–207. doi:10.1038/cdd.2008.170. ISSN   1476-5403. PMC   3272397 . PMID   19023332.
  9. ↑ Boatright, Kelly M; Salvesen, Guy S (2003-12-01). "Mechanisms of caspase activation". Current Opinion in Cell Biology. 15 (6): 725–731. doi:10.1016/j.ceb.2003.10.009. ISSN   0955-0674. PMID   14644197.
  10. ↑ Boatright, Kelly M; Renatus, Martin; Scott, Fiona L; Sperandio, Sabina; Shin, Hwain; Pedersen, Irene M; Ricci, Jean-Ehrland; Edris, Wade A; Sutherlin, Daniel P; Green, Douglas R; Salvesen, Guy S (2 February 2023). "A Unified Model for Apical Caspase Activation". Molecular Cell. 11 (2): 529–541. doi:10.1016/s1097-2765(03)00051-0. ISSN   1097-2765. PMID   12620239.
  11. ↑ "The New Chemical Reporter 6Alkynyl-6-deoxy-GlcNAc Reveals OGlcNAc Modification of the Apoptotic Caspases That Can Block the Cleavage/Activation of Caspase8". doi:10.1021/jacs.7b02213.s001 . Retrieved 2024-10-18.{{cite journal}}: Cite journal requires |journal= (help)
  12. ↑ Baliga, B. C.; Read, S. H.; Kumar, S. (1 November 2004). "The biochemical mechanism of caspase-2 activation". Cell Death & Differentiation. 11 (11): 1234–1241. doi:10.1038/sj.cdd.4401492. ISSN   1476-5403.
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