The Intracellular Chloride Ion Channel Protein CLIC1 Undergoes a Redox-controlled Structural Transition*

By D. Littler, S. Harrop, W. Fairlie, Louise J. Brown, G. Pankhurst, S. Pankhurst, Matthew Z. DeMaere, T. Campbell, A. Bauskin, R. Tonini and 3 more. 2004

237 citations recorded by the source corpus.

Most proteins adopt a well defined three-dimensional structure; however, it is increasingly recognized that some proteins can exist with at least two stable conformations. Recently, a class of intracellular chloride ion channel proteins (CLICs) has been shown to exist in both soluble and integral membrane forms. The structure of the soluble form of CLIC1 is typical of a soluble glutathione S-transferase superfamily protein but contains a glutaredoxin-like active site. In this study we show that on oxidation CLIC1 undergoes a reversible transition from a monomeric to a non-covalent dimeric state due to the formation of an intramolecular disulfide bond (Cys-24–Cys-59). We have determined the crystal structure of this oxidized state and show that a major structural transition has occurred, exposing a large hydrophobic surface, which forms the dimer interface. The oxidized CLIC1 dimer maintains its ability to form chloride ion channels in artificial bilayers and vesicles, whereas a reducing environment prevents the formation of ion channels by CLIC1. Mutational studies show that both Cys-24 and Cys-59 are required for channel activity.

Subfields: Molecular Biology, Nutrition and Dietetics

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Citations in the corpus

Predicting multiple conformations via sequence clustering and AlphaFold2 (2023, neutral): “This fold is stabilized by a disulfide bond between two of the α-helices within the monomer that forms after oxidation 41 .”
Extant fold-switching proteins are widespread (2018, background): “One example is human chloride intracellular channel 1 (CLIC1), a chloride channel that has both cytosolic and membrane-bound conformations (17).”
Ascorbate and Glutathione: The Heart of the Redox Hub1 (2011, background): “This behavior has been described for three DHAR-like chloride intracellular channels in mammals and at least one of the Arabidopsis DHAR proteins (Littler et al., 2004; Elter et al., 2007).”
The changing faces of glutathione, a cellular protagonist. (2003, background): “Moreover, the formation of an intramolecular disulfide bond promotes a structural transition that exposes a large hydrophobic surface changing the monomer into a non-covalent dimer (Littler et al., 2004).”
Mutational tipping points for switching protein folds and functions (2012, background): “, 2008), Mad2 (Luo and Yu, 2008; Mapelli and Musacchio, 2007), and CLIC1 (Littler et al., 2004), suggesting that the phenomenon of fold switching may be more general.”