Caspase-2 (EC3.4.22.55, ICH-1, NEDD-2, caspase-2L, caspase-2S, neural precursor cell expressed developmentally down-regulated protein 2, CASP-2, NEDD2 protein) is an enzyme.[1][2][3][4][5][6] This enzyme catalyses the following chemical reaction
Strict requirement for an Asp residue at P1, with Asp316 being essential for proteolytic activity and has a preferred cleavage sequence of Val-Asp-Val-Ala-Asp-
Caspase-2 is an important enzyme in the cysteine aspartate protease family, known as caspases, which are central to the regulation of apoptosis and, in certain cases, inflammation. While many caspases are mainly involved in the initiation and execution of cell death, caspase-2 has a broader range of functions. Beyond its apoptotic role, it contributes to maintaining genomic stability and responding to cellular stress, demonstrating its multifaceted role in cellular processes and its wider importance in cell regulation mechanisms.[7] When caspases are activated, they break down a variety of specific protein substrates, triggering the distinct features of apoptosis, such as DNA fragmentation, chromatin condensation, and plasma membrane blebbing. Caspase-2, known as the most evolutionarily conserved caspase, holds a unique role in both apoptotic and non-apoptotic functions. Its evolutionary stability highlights its essential contributions to cellular processes like preserving genomic integrity and regulating stress responses, demonstrating its broader significance beyond just apoptosis.[8]
Caspase-2 activation through dimerization.
Caspases are classified into two fundamental groups: initiator caspases, including caspase-8 and caspase-9, and executioner caspases, such as caspase-3 and caspase-7, each playing distinct roles in the apoptosis signaling pathway.[9] Initiator caspases serve as critical regulators at the top of various signaling cascades, orchestrating the activation of executioner caspases through both direct and indirect mechanisms. While these caspases are typically found as inactive monomers within the cell, their activation relies on dimerization. This dimerization occurs when initiator caspases are recruited to large protein complexes that function as intricate signaling platforms, enabling their conversion to an active form.[10] Caspases are produced as single-chain pro-caspases that undergo cleavage within their chains, resulting in the formation of large and small catalytic subunits. Although this cleavage is both necessary and sufficient for activating executioner caspases, evidence indicates that initiator caspases require dimerization for activation. Furthermore, the intra-chain cleavage that follows this process helps to stabilize the active form of the enzyme.[11] Caspase-2 is activated via a mechanism that parallels those of other caspases. In its monomeric state, it shows no measurable activity, regardless of its cleavage status. Conversely, a dimeric form of a cleavage-deficient mutant retains about 20% of its enzymatic activity. Following autoprocessing of the dimerized form, caspase-2 becomes fully active.[12] Consequently, the first step in the activation of caspase-2 is dimerization.
