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C-terminal, alpha helical domain of Chloride Intracellular Channels Glutathione S-transferase (GST) C-terminal domain family, Chloride Intracellular Channel (CLIC) subfamily; composed of CLICs (CLIC1-6 in vertebrates), p64, parchorin, and similar proteins. They are auto-inserting, self-assembling intracellular anion channels involved in a wide variety of functions including regulated secretion, cell division, and apoptosis. They can exist in both water-soluble and membrane-bound states and are found in various vesicles and membranes, and they may play roles in the maintenance of these intracellular membranes. Biochemical studies of the Caenorhabditis elegans homolog, EXC-4, show that the membrane localization domain is present in the N-terminal part of the protein. CLICs display structural plasticity, with CLIC1 adopting two soluble conformations. The structure of soluble human CLIC1 reveals that it is monomeric and adopts a fold similar to GSTs, containing an N-terminal domain with a thioredoxin fold and a C-terminal alpha helical domain. Upon oxidation, the N-terminal domain of CLIC1 undergoes a structural change to form a non-covalent dimer stabilized by the formation of an intramolecular disulfide bond between two cysteines that are far apart in the reduced form. The CLIC1 dimer bears no similarity to GST dimers. The redox-controlled structural rearrangement exposes a large hydrophobic surface, which is masked by dimerization in vitro. In vivo, this surface may represent the docking interface of CLIC1 in its membrane-bound state. The two cysteines in CLIC1 that form the disulfide bond in oxidizing conditions are essential for dimerization and chloride channel activity, however, in other subfamily members, the second cysteine is not conserved. |
Jiyao W et al.(2023). "The conserved domain database in 2023.",