CLV_C14_Caspase3-7

Cysteinyl aspartate specific proteases (caspases) play an important role in development, differentiation, apoptosis and inflammation in metazoa. The 12 known human caspases, members of peptidase family C14, can be classified in 4 groups based on their function and the length of their prodomain. Group I caspases are inflammatory caspases with a large prodomain and includes caspase-1, -4, -5, and -12. Caspases-2, -5, -8, -9, and -10 belong to group II and have also a large prodomain, but initiate apoptosis. Caspase-3, -6, and -7 constitute group III and are effector caspases with a short (20-30 aa) prodomain that execute the apoptotic program by cleavage of various proteins. Caspase-14 is involved in keratinocyte differentiation (Lavrik,2005, Pop,2009). A general characteristic of caspases is their high specificity to cleave C-terminal after aspartate (Stennicke,2000). This primary specificity for aspartate is unique to the granzyme B and caspase families of proteases (Harris,2000). The amino acids N-terminal of the aspartate, mainly the first four, determine the caspase's specificity.
Under normal conditions caspases are present as inactive enzyme precursors (zymogens), the procaspases. They consist of an N-terminal prodomain, the large subunit (p20), an optional linker sequence, and the small subunit (p10). The structure of all caspases is a heterotetramer formed by head-tail organised heterodimers that are composed of the small and the large subunit (Fu,2008, Chai,2001). The caspases' substrate is stabilized by amino acids from both subunits, whereas the catalytic dyad is localised within the large subunit and consists of a cysteine and a histidine (Wilson,1994). In vivo active initiator caspase-8, -9, and -10 and the lymphocyte-specific serine protease granzyme B perform proteolytic activation of the caspase-3 and -7 zymogen dimer by cleavage of the prodomain and the inhibiting linker. This activation can occur by two different mechanisms: the extrinsic and the intrinsic pathway. In the extrinsic or death receptor-mediated pathway death receptor ligands induce the oligomerization of death receptor (CD95 or TRAIL-R1/R2) resulting in the formation of the death-inducing signalling complex (DISC). Caspase-8 and -10 are activated by DISC and cleave caspase-3 and -7. The intrinsic or mitochondria-mediated pathway is induced by stimuli such as DNA damage, cytotoxic stress, and heat shock leading to the release of cytochrome C from the mitochondria and the formation of the apoptosome. After its activation by the apoptosome caspase-9 processes caspase-3 and -7 (Jiang,2000). Executor caspases-3 and -7 cleave a variety of downstream proteins resulting in membrane blebbing, pyknotic nuclei, cell rounding, formation of apoptotic vesicles, and finally in apoptotic cell death.
Non-apoptotic activities of caspases including involvement in immune response (Zhang,1998), proliferation (Woo,2003), differentiation (Zermati,2001, Carlile,2004), and cell motility (Barnhart,2004) are also described. However little is known about this, particularly the control and regulation of specific caspase cleavage. Regulation of caspases' non-apoptotic activities presumably occurs by post-translational modification of the caspases and/or the substrates, subcellular compartmentalisation of caspases, protection of potential substrates by scaffold proteins or protein complexes, activation of anti-apoptotic factors, and recruitment of antagonistic proteins at the level of caspase activation complexes (Launay,2005, Yi,2009).
Due to their ability to induce apoptotic cell death, the activation of caspases and active caspases are modulated and/or inhibited by a number of regulatory mechanisms. The activation of caspase-8 at the DISC can be modulated by cellular FLICE-inhibiting protein (cFLIP), a member of the DISC (11713262). Inhibition of apoptosis protein (IAP) family inhibits the enzymatic activities of caspases using baculoviral IAP repeats (LIG_BIR_II_1, LIG_BIR_III_1, LIG_BIR_III_2, LIG_BIR_III_3, LIG_BIR_III_4) (Deveraux,1999). The most prominent IAP XIAP inhibits caspase-3, -7 and -9. It interacts with the N-terminal of the small caspase subunit and shields the catalytic side of caspase-3 and -7 by reverse binding (Eckelman,2006). Two other natural, viral pan-caspase inhibitors are known: p35 (Xu,2001) and CrmA (Renatus,2000).