Caspase molecules are a class of protease molecules that have been very conservative in evolution. The enzyme has a variety of subtype structures, the most common of which are Caspase-2 and Caspase-3. Detection of them can also be used to distinguish tumor cells.
Figure 1. Structure of caspase-1 (CASP1).
The meaning of Caspase is that they are cysteine proteases and use cysteine as a nucleophilic group when cleavage the substrate. They are aspartic proteases, which cleave peptide bonds formed between the carboxyl group of aspartic acid and the amino group of the next amino acid. People's understanding of the important role of Caspase in apoptosis comes from some experimental observations: Natural and synthetic Caspase inhibitors can significantly reduce or even block apoptosis caused by various stimuli. Some animal models of Caspase gene knockout show obvious apoptotic phenomenon. Caspase catalyzes the cleavage of numerous intracellular functional protein molecules that can cause apoptosis. In addition to the important role of Caspase in the process of apoptosis, it also plays an important role in the process of inflammation. Caspase molecules are synthesized in the form of zymogens and are constitutively expressed at low levels in the body. External or internal stimuli cause Caspase molecules to activate in a waterfall-like manner. Activated Caspase molecules catalyze the cleavage of numerous effector molecules and induce apoptosis.
Examples of Caspase Proteins
Caspase-1 is an evolutionarily conserved enzyme that can proteolytically cleave other proteins (such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 and the pyrolysis inducer Gasdermin D) into active mature peptides. As an initiator of inflammatory response, it plays a central role in cellular immunity. Once activated by the formation of an inflammasome complex, it triggers a pro-inflammatory response through cleavage, which activates two inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18) and programmed lysis Cell pyrolysis. Caspase-1 activated two inflammatory cytokines are excreted from the cell, further inducing an inflammatory response in neighboring cells.
Figure 2. Structure of the CASP1 protein.
Caspase 2 (also known as CASP2) is an enzyme encoded by the CASP2 gene in humans. Caspase 2 proteolytically cleaves other proteins. It belongs to the family of cysteine proteases called caspases, which cleaves proteins only at amino acids after aspartic acid residues. In this family, caspase 2 is part of the Ich-1 subfamily. It is one of the most conserved caspases in different animal species. Overall, caspase 2 appears to be a very versatile caspase with multiple functions beyond cell death induction.
Figure 3. Structure of the CASP2 protein.
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 many mammals where complete genomic data are available. Unique orthologs also exist in birds, lizards, amphibians and teleosts. CASP3 protein is a member of the cysteine-aspartic protease (caspase) family. The sequential activation of cysteine proteases plays a central role in the execution phase of apoptosis. Caspase exists as an inactive enzyme and undergoes proteolytic treatment at conserved aspartic acid residues, producing two large and small subunits that dimerize to form an active enzyme. This protein cleaves and activates caspase 6 and 7; and the protein itself is processed and activated by cysteine proteases 8, 9 and 10. This is the main caspase, involved in the cleavage of the β-amyloid 4A precursor protein, and is associated with neuronal death in Alzheimer's disease. Alternative splicing of this gene results in two transcript variants encoding the same protein.
Figure 4. Caspase-3 heterotetramer + 2 pryazinone inhibitor (green-red), Human.
Caspase-6 is an enzyme encoded by the CASP6 gene in humans. CASP6 orthologs have been identified in many mammals where complete genomic data are available. Unique orthologs also exist in birds, lizards, amphibians and teleosts. Caspase-6 has known functions in apoptosis, early immune response and neurodegenerative changes in Huntington's disease and Alzheimer's disease.
Figure 5. Structure of protein CASP6.
Role in inflammation
Inflammation is a protective attempt by an organism to restore homeostasis after it is damaged by harmful stimuli such as tissue damage or bacterial infection. Caspase-1 is the key to activating pro-inflammatory cytokines. These serve as signals for immune cells, enabling the environment to facilitate the recruitment of immune cells to the damaged site. Therefore, Caspase-1 plays a fundamental role in the innate immune system. This enzyme is responsible for processing and secreting cytokines such as pro-ILβ and pro-IL18. Human Caspase-4 and -5, and mouse Caspase-11 have a unique receptor function, which binds to LPS, a molecule rich in Gram-negative bacteria. Activation of Caspase-1 can lead to the processing and secretion of IL-1β and IL-18 cytokines. This downstream effect is the same as described above. It also causes the secretion of another untreated inflammatory cytokine. This is called pro-IL1α. There is also an inflammatory caspase-11 that helps in the secretion of cytokines. This is done by inactivating a membrane channel that blocks IL-1β secretion. Caspase can also induce an inflammatory response at the transcription level. There is evidence that it can promote the transcription of nuclear factor-κB (NF-κB), a transcription factor that helps to transcribe inflammatory cytokines such as IFN, TNF, IL-6 and IL-8. For example, Caspase-1 activates Caspase-7, which in turn cleaves poly (ADP) ribose-which activates the transcription of the NF-κB control gene.