Effect of a Procaspase-Activating Compound on the Catalytic Activity of Mature Caspase-3

Abstract

Caspase-3, an apoptosis-executing enzyme with a dimeric structure, and its zymogen (procaspase-3) are target proteins in cancer chemotherapy using synthetic compounds. Previous work has shown that PAC-1 (1st procaspaseactivating compound) affects the activation of procaspase-3 in cancerous cells through the Zn 2+ -chelation mechanism. However, we found that the compound also enhances the mature caspase-3 activity in the absence of Zn 2+. The enhancement of the mature caspase-3 activity by PAC-1 followed a MichaelisMenten-type saturation dependency with respect to the concentration of the compound. PAC-1 induced the change in the UVvis spectrum of the mature caspase-3. From these findings, we propose a direct structural interaction of PAC-1 with the protein core. According to a molecular dynamics calculation for the complex of PAC-1 and mature caspase-3, PAC-1 is likely to bind to the interface between the dimeric structure in mature caspase-3. The interactions between PAC-1 and amino acid residues that affect the catalytic activity of mature caspase-3 are suggested. Throughout this work, diverse functions of the apoptosis-inducing compound are disclosed.