Probing the control and action of CLIC1/NCC27, an unusual chloride ion channel, by x-ray crystallography

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Cells must regulate the flow of ions and water across their membranes in order to survive and function normally. The balance of ions and water is controlled by ion channels - proteins that control the permeability of the cell membrane. Of the ion channels, chloride channels are the most abundant in cells. They are central to the functioning of normal cells as well as playing a key role in many disease states. Our group was the first to identify and characterise a new class of chloride channel which plays a key roles in the regulation of the immune system. These channels are unusual in that they can move between two states: a soluble state and a state that resides in the cell membrane. We have determined the first structure of this class of channel in the soluble state. In this project, we will determine: how the protein makes the transition into the membrane state; which factors control this transition; and the structure of the protein in the membrane state. We will also determine how several drugs control the activity of this channel. The results of our work will have specific implications for our channel and will serve as a paradigm for other members of this new class of chloride channel. Understanding how this channel functions and how the current drugs control it will lead to the development of a new class of therapeutic agents that will control these channels by preventing the transition from the soluble to the membrane state.