Fig. 8: Phosphorylation at S384 affects the conformation of the substrate binding pocket.

a The crystal structure of human active caspase-2/VDVAD (PDB ID: 3R6G) [41] complex. Crystalised caspase-2 is composed of two p19/p12 heterodimers. b Magnified view showing position of S384 and surrounding amino acid residues important for substrate binding. T380 and Y420 and W385 are shown in magenta and interact with P5 and P4 residues [41]. S384 and C320 are shown in orange and red, respectively. c Schematic showing regulation of caspase-2 by AURKB-mediated phosphorylation in mitosis. During normal mitosis, S384 of caspase-2 is phosphorylated by AURKB, maintaining caspase-2 in inactive state. In response to aberrant mitosis, such as cytokinesis failure and chromosome missegregation, reduced AURKB activity enables S384 dephosphorylation by protein phosphatase(s) (PP). This leads to caspase-2 activation that can result in two outcomes: either cleavage of MDM2, which leads to p53 stabilisation and cell cycle arrest, or cleavage of Bid, which leads to outer mitochondrial membrane permeabilization (MOMP), caspase-3 activation and apoptotic cell death. Increased AURKB levels (and reduced caspase-2 activation) are associated with chromosome instability. Therefore, these caspase-2 activation pathways limit cells becoming aneuploid or polyploid, preventing chromosome instability. Dashed lines indicate unknown mechanisms.