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
| Caspase-2 | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| EC no. | 3.4.22.55 | ||||||||
| CAS no. | 182372-14-1 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| |||||||||
- 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.
editCaspases 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.
References
edit- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ "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. PMC 6225779. Retrieved 2024-10-18.
{{cite journal}}: Cite journal requires|journal=(help) - ^ 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.
External links
edit- Caspase-2 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
