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on human caspase-2 indicate that it forms a p19/p12 homodimer
in solution with two active sites [ 14 ]. Interestingly the caspase-2
dimer has an intersubunit disulfi de bridge between two adjacent
cysteine residues (Cys^329 –Cys^390 ), which is proposed to be impor-
tant for caspase-2 dimerization and activation. As a consequence of
its ability to readily dimerize in solution, caspase-2 can autoactivate
when overexpressed in cultured cells [ 1 , 4 ]. The unique structure
of its active site confers somewhat atypical substrate specifi city for
caspase-2. Unlike other caspases, caspase-2 substrate recognition
requires a pentapeptide sequence (XDxxD), with an additional
small hydrophobic P5 residue (X) that accommodates a unique
hydrophobic S5 binding pocket in the binding groove of the cas-
pase- 2 dimer [ 14 , 15 ].
Caspase-2 is classed as an initiator caspase which acts upstream
of mitochondrial outer membrane permeabilization (MOMP) [ 7 ,
16 , 17 ]. When activated, caspase-2 cleaves several cellular targets
including Bid, Mdm2, and ICAD [ 2 ]. Caspase-2-mediated cleav-
age of Bid induces MOMP and apoptosis [ 16 – 19 ]. Caspase-2 has
been shown to be required for apoptosis induced by cytotoxic drugs
and DNA-damaging agents [ 20 , 21 ], TRAIL [ 22 ], heat shock
[ 19 ], cytoskeletal disruption [ 20 ], and in oocyte cell death in
response to nutrient deprivation [ 23 – 26 ]. Caspase-2 activation in
cells is commonly monitored and detected following these apopto-
sis stimuli. However, its importance in apoptosis remains somewhat
contentious as Caspase-2 −/−^ ( Casp2 −/−^ ) mice are viable and fertile with
only minor apoptotic defects in some cell types [ 20 , 24 , 25 , 27 ].Fig. 1 Schematic representation of caspase-2 structure and activation. Caspase-2 zymogen exists as a monomer.
In response to apoptotic stimuli, pro-caspase-2 molecules dimerize via their CARD and this leads to cleavage
between the large (p19) and small (p14) enzyme subunits at D333. This cleavage event results in the formation
of an active stable tetrameric complex. Further processing of this complex at D169 and D347 can also occur
by caspase-3 to generate fully mature caspase-2 enzyme. NLS, nuclear localization sequence ( yellow line );
C320, catalytic cysteine residue ( red line )
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