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专注多肽 服务科研
Definition
Caspases are a family of aspartate specific cysteine proteases that play an important role in apoptosis, necrosis and inflammation1.
Discovery
Caspases were first identified in the nematode C. elegans. It was found that the gene ced-3 was required for cell death during C.elegans development2. In 1993, the protein encoded by the ced-3 gene was identified as a cysteine protease and it was found that it had similar properties to the mammalian interleukin-1-beta converting enzyme (ICE) (now known as caspase 1) which at the time was the only known caspase3. Other mammalian caspases were subsequently identified.
Classification
There are three types of apoptotic caspases: initiator, effector and inflammatory caspases. Initiator caspases (e.g. CASP2, CASP8, CASP9 and CASP10) cleave inactive pro-forms of effector caspases, thereby activating them4. Effector caspases (e.g. CASP3, CASP6 and CASP7) in turn cleave other protein substrates within the cell, to trigger the apoptotic process4. Inflammatory caspases are involved in immune response (e.g. CASP1, CASP4, CASP5, CASP11, CASP12 and CASP13). Caspase inhibitors regulate the initiation of this cascade4.
Structural Characteristics
Caspases are synthesized as inactive zymogens or procaspases. Activation of caspases occurs by cleavage of the prodomain in the procaspases5. The caspase catalytic domain is composed of a twisted, mostly parallel ß-sheet sandwiched between two layers of a-helices. Also they contain an active cysteine residue in their catalytic domain5. In addition to the catalytic domain, both inflammatory and initiator caspases carry at their N-termini, one or two copies of CARD or DED modules, which are critical for their activation in vivo. These modules are mainly composed of six antiparallel a-helices, with helices a1–a5 building an a-helical Greek key5. The general structure of a caspase inhibitor is [tetrapeptide]-CO-CH2-X, that binds to the Cys285 in the active site of caspases5.
Mode of action
Caspases cleave the substrate after an Asp residue6. There are several hundred substrates for caspases. Initially activation of initiator caspases occurs as a result of an extrinsic or intrinsic death signal6. Activated initiator caspases cleave effector caspases that in turn cleave the substrate at an Asp residue6. For example, caspase-8 cleaves the pro-apoptotic protein Bid that gets activated and translocates into the mitochondria where it activates other pro-apoptotic proteins, Bax and Bak thus amplifying the death signal6.
Functions
Caspases such as caspase-1 are involved in the activation of pro-inflammatory cytokines such as Interleukin 1 and interleukin 185,6. Caspases play an important role in apoptosis. One of the hallmark feature of apoptotic cell death is genomic disassembly and proteolysis5,6. By cleaving their substartes, caspases inactivate cell cycle progression and DNA repair processes. They also activate several pro-apoptotic proteins5,6. In some cases Caspases’ role in aberrant processing events has shown their involvement in neurodegenerative disorders such as Huntington disease and Alzheimer’s disease6. Some of the final targets of caspases include: nuclear lamins, ICAD/DFF45 (inhibitor of caspase activated DNase or DNA fragmentation factor 45), PARP (poly-ADP ribose polymerase) and PAK2 (P 21-activated kinase 2)6. Caspases are also implicated in embryonic development and T and B cell differentiation7.
References
1. Book: Cells by Benjamin L, Lynne C, Vishwanath RL, George P (207), 536-540.
2. Ellis HM, Horvitz HR (1986). Genetic control of programmed cell death in the nematode C. elegans. Cell, 44(6), 817-29.
3. Yuan J, Shaham S, Ledoux S, Ellis HM and Horvitz HR (1993). The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell 75: 641–652.
4. Salvesen GS, Riedl SJ (2008). Caspase mechanisms. Adv Exp Med Biol., 615, 13-23.
5. Prior PF and Salvesen GS (2004). The protein structures that shape caspase activity, specificity,activation and inhibition. Biochem. J., 384, 201–232.
6. Nicholson DW (1999). Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death and Differentiation, 6, 1028 ± 1042.
7. Maelfait J, Beyaert R (2008). Non-apoptotic functions of caspase-8. Biochem Pharmacol., 76(11), 1365-73.
