Caspase-7: a protease involved in apoptosis and inflammation

Abstract

Caspase-7 was considered to be redundant with caspase-3 because these related cysteine proteases share an optimal peptide recognition sequence and have several endogenous protein substrates in common. In addition, both caspases are proteolytically activated by the initiator caspase-8 and -9 during death receptor- and DNA-damage-induced apoptosis, respectively. However, a growing body of biochemical and physiological data indicate that caspase-7 also differs in significant ways from caspase-3. For instance, several substrates are specifically cleaved by caspase-7, but not caspase-3. Moreover, caspase-7 activation requires caspase-1 inflammasomes under inflammatory conditions, while caspase-3 processing proceeds independently of caspase-1. Finally, caspase-7 deficient mice are resistant to endotoxemia, whereas caspase-3 knockout mice are susceptible. These findings suggest that specifically interfering with caspase-7 activation may hold therapeutic value for the treatment of cancer and inflammatory ailments.

Figure 1

Overview of caspase activation mechanisms. Caspases are activated in a two-step cascade, with initiator caspases (caspase-1, -8, -9 and -10) being first activated in large cytosolic protein complexes by proximity-induced autoactivation. Caspase-8 and -10 are activated in the death-inducing signaling complex (DISC) following death receptor stimulation, caspase-9 in the apoptosome in response to genotoxic stress, and caspase-1 in the inflammasome complex under inflammatory conditions. Activated initiator caspases directly activate the executioner caspases-3 and/or -7, which lead to apoptosis or inflammation by cleaving specific sets of substrates.

Figure 2

Structure of procaspase-7. (A) Schematic representation of the procaspase-7 and active caspase-7 homodimer (shown in green and blue, respectively). The identity and position of the first (M₁) and last (Q₃₀₃) residues of the procaspase-7 amino acid sequence are indicated. The active site cystein residue Cys186 is shown in red. Initiator caspases cleave procaspase-7 after Asp₂₃, which is located between the propeptide and the p20 subunit. The linker region between the p20 and p10 subunits is removed by cleavage after Asp₁₉₈ and Asp₂₀₆. Proteolytic removal of the propeptide and linker sequences leads to the active caspase-7 homodimer. (B) Three-dimensional structure of procaspase-7 (PDB entry 1K88) with the monomers of the homodimer shown in green and blue, respectively. The active site Cys186 is shown in red and space fill. (C) Three-dimensional structure of procaspase-7 (PDB entry 1K88) with backbone coloring by secondary structure. The positions of the flexible L1-L4 loops, which form the catalytic groove and substrate binding pockets, are indicated. The active site Cys186 is shown in red and space fill.