Evolution of an allosteric "off switch" in apoptotic caspases

Abstract

Caspase-3 is well known as the "executioner" whose activation commits the cell to an apoptotic fate, but low levels of caspase-3 activity also play key roles in development. A new study explains how cells can balance these functions, using biophysical, structural, and computational approaches to demonstrate the mechanism by which phosphorylation of conserved sites on a distal surface loop reduces or abolishes catalytic activity. These results provide new insights into allosteric regulation mechanisms and offer new opportunities for development of caspase-3 modulators.

Keywords: allosteric regulation; apoptosis; caspase; phosphorylation; protein evolution.

Figure 1.

Caspase-3 catalytic activity can be allosterically modulated by phosphorylation at Ser¹⁵⁰ or Thr¹⁵². The caspase-3 dimer (Protein Data Bank code 2J30) is illustrated with one protomer shown as a white surface and the other as a light blue surface. Active sites are shown with the Ac-DEVD-CMK inhibitor as colored spheres, with orange carbon atoms. Conformational changes that occur upon phosphorylation of Ser¹⁵⁰ or Thr¹⁵² (colored spheres with blue carbon atoms) are propagated to the active sites through distinct intraprotomer (red bar-headed arrow) or interprotomer (blue bar-headed arrow) pathways.