Structural basis for ion conduction and gating in ClC chloride channels

Members of the CIC family of voltage-gated chloride channels are found from bacteria to mammals with a considerable degree of conservation in the membrane-inserted, pore-forming region. The crystal structures of the CIC channels of Escheriehia coli and Salmonella typhimurium provide a structural framework for the entire family. The CIC channels are homodimeric proteins with an overall rhombus-like shape. Each CIC dimer has two pores each contained within a single subunit. The CIC subunit consists of two roughly repeated halves that span the membrane with opposite orientations. This antiparallel architecture defines a chloride selectivity filter within the 15-Angstrom neck of a hourglass-shaped pore. Three Cl- binding sites within the selectivity filter stabilize ions by interactions with a-helix dipoles and by chemical interactions with nitrogen atoms and hydroxyl groups of residues in the protein. The Cl- binding site nearest the extracellular solution can be occupied either by a Cl- ion or by a glutamate carboxyl group. Mutations of this glutamate residue in Torpedo ray CIC channels alter gating in electrophysiological assays. These findings reveal a form of gating in which the glutamate carboxyl group closes the pore by mimicking a Cl- ion. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.