Caspase-3/Sandbox: Difference between revisions

(Structural insights into its function)

[[Image:Apoptosis pathway.png|360px|left]]  

Caspases are proteases that function via a cysteine residue in the active site to cleave substrates after aspartic acid residues. Caspases are crucial for the initiation (e.g. caspase-8, -9, -10) and execution (e.g. caspase-3, -6, -7) of apoptosis, or programmed cell death either via the intrinsic or extrinsic pathway (Degterev, Boyce et al. 2003).  In the intrinsic pathway, stimuli such as trophic factor withdrawal, UV irradiation, chemotherapeutics, DNA damage, endoplasmic reticulum (ER) stress, activates B cell lymphoma 2 (BCL-2) homology 3 (BH3)-only proteins like Bim or Bad, leading to BCL-2-associated X protein (BAX) and BCL-2 antagonist or killer (BAK) activation and mitochondrial outer membrane permeabilization (MOMP). Anti-apoptotic BCL-2 proteins prevent MOMP by binding BH3-only proteins and activated BAX or BAK. Following MOMP, release of various proteins from the mitochondrial intermembrane space (IMS) promotes caspase activation and apoptosis. Cytochrome c binds apoptotic protease-activating factor 1 (APAF1), inducing its oligomerization and thereby forming a structure termed the apoptosome that recruits and activates an initiator caspase, caspase-9. Caspase-9 cleaves and activates effector caspases, caspase-3 and caspase-7, leading to apoptosis through cleavage of death substrates such as Inhibitor of Caspase-activated Deoxyribonuclease (ICAD) and Poly ADP ribose polymerase (PARP). Mitochondrial release of second mitochondria-derived activator of caspase (SMAC; also known as DIABLO) and OMI (also known as HTRA2) neutralizes the caspase inhibitory function of X-linked inhibitor of apoptosis protein (XIAP). The extrinsic apoptotic pathway is initiated by the ligation of death receptors with their cognate ligands, leading to the recruitment of adaptor molecules such as Fas-associated death domain protein (FADD) and then caspase-8. This results in the dimerization and activation of caspase-8, which can then directly cleave and activate caspase-3 and caspase-7, leading to apoptosis. Crosstalk between the extrinsic and intrinsic pathways occurs through caspase-8 cleavage and activation of the BH3-only protein BH3-interacting domain death agonist (BID), the product of which (truncated BID; tBID) is required in some cell types for death receptor-induced apoptosis (Li, Zhu et al. 1998). It has become appreciated more recently that caspase activity, specifically caspase-8, is also required for T cell growth (Alam, Cohen et al. 1999; Kennedy, Kataoka et al. 1999; Misra, Jelley-Gibbs et al. 2005), and that the location and level of active caspases within cells may be a key determinant of survival or death (Misra, Russell et al. 2007; Koenig, Russell et al. 2008).  We have previously observed that murine αβ T cells bearing high levels of caspase activity manifest increased rates of both cell growth and cell death (Dohrman, Russell et al. 2005).  

====Caspase-3====

[[Image:ICAD.png|300px|right]]

In its inactive form, procaspase-3 consist of a large subunit and small subunit, interjected by an aspartic acid residue. This aspartate is the site recognized by activated initiator caspases, such as caspase-8 and caspase-9. Upon cleavage, procaspase-3 is separated into two subunits, p18/20 and p12/10 respectively, which heterodimerize to yield the active form of caspase-3. In its active form, caspase-3 is able to cleave substrates such as ICAD (inhibitor of caspase-activated deoxyribonuclease). Cleavage of ICAD leads to abrogation of its inhibitory effect on CAD, allowing CAD to migrate into the nucleus and cause double-strand breaks in DNA, thus contributing to apoptosis(Enari, Sakahira et al. 1998; Sakahira, Enari et al. 1998).  

==Disease==

Although the role of caspases in chronic neurodegenerative disease is controversial, their role in acute neurodegenerative disease, such as nerve crush injury and stroke, may be more evident. Inhibition of caspase activity increases survival of neurons.  

To date, eighteen caspases have been identified. Caspases can largely be grouped into three subfamilies in humans: inflammatory (caspase-1, -4, and -5), effector (caspase-3, -6, and -7), and initiator caspases (-2, -8, -9, and -10). Caspase-11 and -12 substitutes for caspase-4 and -5, respectively, in mice. (Fuentes-Prior and Salvesen, 2004)