Unique structure and function of chloride transporting CLC proteins.
CLC proteins are a large structurally defined family of Cl- ion channels and H+/Cl- antiporters with nine distinct genes in mammals. The membrane-embedded part of CLC proteins bears no obvious similarity to any other class of membrane proteins, while the cytoplasmic C-terminus of most eukaryotic and some prokaryotic CLCs contains two regions with homology to cystathionine beta synthase (CBS) domains that are found in other proteins as well. Different members serve a broad range of physiological roles, including stabilization of the membrane potential, transepithelial ion transport, and vesicular acidification. Their physiological importance is underscored by the causative involvement in at least four different human genetic diseases. From functional studies of the Torpedo homologue ClC-0, a homodimeric architecture with two physically separate ion conduction pathways was anticipated and fully confirmed by solving the crystal structure of prokaryotic CLC homologues. The structure revealed a complex fold of 18 alpha-helices per subunit with at least two Cl- ions bound in the center of each protopore. A critical glutamic acid residue was identified whose side-chain seems to occupy a third Cl- ion binding site in the closed state and that moves away to allow Cl- binding. While the overall architecture and pore structure is certainly conserved from bacteria to humans, the bacterial proteins that were crystallized are actually not Cl- ion channels, but coupled H+/Cl- antiporters. These recent breakthroughs will allow us to study in further detail the structure, function, and the physiological and pathophysiological role of CLC proteins.
Pusch
Michael
M
Institute of Biophysics, Italian Research Council, Genoa I-16149, Italy. pusch@ge.ibf.cnr.it
Jentsch
Thomas J
TJ
D000818:Animals; D001693:Biological Transport, Active / Q000502:physiology; D002462:Cell Membrane / Q000737:chemistry / Q000502:physiology; D002463:Cell Membrane Permeability / Q000502:physiology*; D018118:Chloride Channels / Q000737:chemistry* / Q000502:physiology*; D002713:Chlorine / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D018118:Chloride Channels; D008051:Lipid Bilayers; D002713:Chlorine