Pore-Forming Proteins with Built-in Triggers and Switches

The self-assembling, pore-forming protein oi-hemolysin is a monomeric, 293-amino-acid, water-soluble polypeptide that forms heptameric pores of 1- to 2-nm internal diameter in lipid bilayers. By genetic engineering and targeted chemical modification, we have produced α-hemolysins in which pore-forming activity can be triggered or switched on and off by biochemical, chemical. or physical stimuli. These remodeled molecules include protease activated pores, metal-regulated pores, pores that are activated by chemical alkylation, and pores that are turned on with light. Engineered α-hemolysins have potential applications that include acting as components of sensors for various analytes, mediating the controlled release of drugs and forming building blocks for agents that selectivity damage malignant cells.