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Caspase & inhibitor Proteins

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Caspase & inhibitor Proteins

Caspase & inhibitor Proteins Background

Caspase molecules are a class of protease molecules that are evolutionarily very conserved. The enzyme has a variety of subtype structures, the most common of which is Caspase-2, Caspase-3 type. Their detection can also be used to distinguish between detection of tumor cells.

The meaning of Caspase is manifested in two aspects:

1 They are cysteine ​​proteases and use cysteine ​​as a nucleophilic group upon cleavage of the substrate.

2 They are aspartic proteases, which cleave peptide bonds formed by 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:

1. Natural and synthetic Caspase inhibitors can significantly reduce or even block apoptosis caused by multiple stimuli.

2. Some Caspase knockout animal models showed significant apoptosis-free phenomenon.

3. Caspase catalyzes the cleavage of numerous intracellular functional protein molecules that can cause apoptosis.

In addition to its important role in the process of apoptosis, Caspase molecules also play an important role in the inflammatory process. Caspase molecules are synthesized in the form of zymogens and are constitutively expressed at low levels in vivo. External or internal stimuli cause the Caspase molecules to activate in a waterfall-like manner. Activated Caspase molecules catalyze the cleavage of numerous effector molecules and induce apoptosis.

Figure 1. This is a structure of interleucin 1-β converting enzime (caspase 1).

Activation of caspase

Caspase is synthesized as an inactive zymogen (pre-caspase) that is only activated by appropriate stimulation. This post-translational level of control allows for rapid and rigorous regulation of the enzyme. Activation involves dimerization and frequent oligomerization of caspase, followed by cleavage into small subunits and large subunits. The large subunit and the small subunit associate with each other to form an active heterodimeric caspase. Active enzymes are typically present in the biological environment as heterotetramers, and pro-caspase dimers are cleaved together to form heterotetramers.

Role in inflammation

Inflammation is a protective attempt by an organism to restore homeostasis after being destroyed by harmful stimuli such as tissue damage or bacterial infection.

Caspase-1, Caspase-4, Caspase-5 and Caspase-11 are considered to be "inflammatory caspase".

Caspase-1 is the key to activating pro-inflammatory cytokines. These signals, which serve as immune cells, allow the environment to facilitate the recruitment of immune cells to damaged sites. Therefore, Caspase-1 plays a fundamental role in the innate immune system. This enzyme is responsible for the treatment of cytokines such as pro-ILβ and pro-IL18 and secretes them.

Human Caspase-4 and Caspase-5, mouse Caspase-11 have a unique receptor role, which binds to LPS, a molecule rich in Gram-negative bacteria. By activating Caspase-1, it 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. The caspase-11, also an inflamed caspase, contributes to the secretion of cytokines. This is done by inactivating the membrane channel that blocks the secretion of IL-1β. Caspase can also induce an inflammatory response at the transcriptional level. There is evidence that it promotes transcription of nuclear factor-kappa B (NF-κB), a transcription factor that facilitates the transcription of inflammatory cytokines such as IFN and TNF. For example, Caspase-1 activates Caspase-7, which in turn cleaves poly (ADP) ribose - this activates transcription of NF-κB (Figure 2)regulatory genes.

Figure 2. Mechanism of NF-κB action.

Inhibitor Proteins

The inhibitor protein (IP) is situated in the mitochondrial matrix and protects the cell against rapid ATP hydrolysis during momentary ischaemia. In oxygen absence, the pH of the matrix drops. This causes IP to become protonated and change its conformation to one that can bind to the F1Fo synthetase and stops it thereby preventing it from moving in a backwards direction and hydrolyze ATP instead of make it. When oxygen is finally incorporated into the system, the pH rises and IP is deprotonated. IP dissociates from the F1Fo synthetase and allows it to resume its ATP synthesis.

References:

1. Wilson KP.; et al. Structure and mechanism of interleukin-1 beta converting enzyme. Nature. 1994, 370 (6487): 270–5.

2. Rathore, S.; et al. Disruption of cellular homeostasis induces organelle stress and triggers apoptosis like cell-death pathways in malaria parasite. Cell Death & Disease. 2015. 6 (7): e1803.

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