Apoptosis zymogens

A proteolytic cascade occurs when one peptidase activates the next in a proteolytic pathway, and this in turn activates the next and so on. This is a mechanism to amplify the initial signal, because one peptidase molecule can activate many zymogen molecules. Examples of proteolytic cascades include blood coagulation, activation of digestive peptidases in the intestine, and apoptosis. 

Interactions between serine proteases are common, and substrates of serine proteases are usually other serine proteases that are activated from an inactive precursor [66]. The involvement of serine proteases in cascade pathways is well documented. One important example is the blood coagulation cascade. Blood clots are formed by a series of zymogen activations. In this enzymatic cascade, the activated form of one factor catalyzes the activation of the next factor. Very small amounts of the initial factors are sufficient to trigger the cascade because of the catalytic nature of the process. These numerous steps yield a large amplification, thus ensuring a rapid and amplified response to trauma. A similar mechanism is involved in the dissolution of blood clots. A third important example of the coordinated action of serine proteases is the intestinal digestive enzymes. The apoptosis pathway is another important example of coordinated action of other types of proteases. 

Caspases are the main proteins involved in the execution of apoptosis (Troy and Salvesen, 2002). They are a family of cysteine aspartate proteases with a conserved QACXG motif at the active site. To date, 13 mammalian caspases have been identified (Lamkanfi et al., 2002). Synthesized as inactive precursors or zymogens, they can be classified based on their structure, mode of activation, cleavage specificity, and function. According to their function caspases can be subdivided into three groups, shown in Fig. 1 ... 

The caspase gene family contains 14 mammalian members of these, 11 human enzymes have been identified (Table 1). This gene family is composed of two major subfamilies ICE (caspase-1 inflammation group) and ICH (ICE and Ced-3 homologue apoptosis group) [13]. All the caspases share similarities in their amino acid sequence, structure, and substrate specificity. They are expressed as proenzymes or zymogens... 

Caspases are proteolytic enzymes that have a critical role in programmed cell death (also called apoptosis) (see Chapter 16). Caspases are present as latent zymogens until their autoproteolysis (self-cleavage) is activated by "death signals" to the receptor complex. Once activated, they work systematically to dismantle a cell through degrading a wide variety of proteins, such as DNA repair enzymes and cellular structural proteins. 

Mitochondria and Apoptosis The loss of mitochondrial integrity is a major route initiating apoptosis (see Chapter 18, section V). The intermembrane space contains procaspases —2, —3, and 9, which are proteolytic enzymes that are in the zymogen form (i.e., must be proteolytically cleaved to be active). It also contains apoptosis initiating factor (AIF) and caspase-activated DNAase (CAD). Cytochrome c, which is loosely bound to the outer mitochondrial membrane, may also enter the intermembrane space when the electrochemical potential gradient is lost. The release of cytochrome c and the other proteins into the cytosol initiates apoptosis. 

Caspases, a family of aspartate-specific cysteine proteases, are essential in the initiation and execution of apoptosis (Creagh et al., 2003 Cohen, 1997). They are expressed as inactive proenzymes (zymogens) that become active during apoptosis. Out of 14 caspase enzymes, caspase-3 appears to be the major effector of neuronal apoptosis induced by a variety of stimuli as well as traumatic injuries (Fig. 4.4). A role for caspase-3 in injury-induced neuronal cell death has been established using semispecific peptide caspase inhibitors. Caspases not only cleave other downstream caspases but also a variety of enzymes, cytokines, cytoskeletal, nuclear, and cell cycle regulatory proteins (Cohen, 1997). Their activities in brain and spinal cord tissues are regulated by the occurrence in zymogens form, by members of Bcl-2 family, and certain cellular inhibitor of apoptosis proteins (cIAPs). 

Caspases are a family of at least 14 aspartate-specific cysteine proteases that are essential in the initiation and execution of apoptosis (Creagh et al., 2003 Cohen, 1997). Caspases are normally expressed as inactive proenzymes (zymogens) that become activated during apoptosis (Zhivotovsky et al., 1999). All members of the caspase family share a number of amino acid residues crucial for substrate binding... 

Caspases are a family of speciflc proteases, present as inactive precursors in growing cells which trigger apoptosis [18]. These proteases use a cysteine residue for catalysis and only cleave substrates at Asp-Xxx bonds [19]. Caspases are synthesized as zymogens with an N-terminal prodomain, followed by a large and... 

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