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Computational Analysis of the Soluble Form of the Intracellular Chloride Ion Channel Protein CLIC1

Authors :
Anthony M. George
Paul M. G. Curmi
Stella M. Valenzuela
Peter M. Jones
Source :
BioMed Research International, Vol 2013 (2013), BioMed Research International
Publication Year :
2013
Publisher :
Hindawi Limited, 2013.

Abstract

The chloride intracellular channel (CLIC) family of proteins has the remarkable property of maintaining both a soluble form and an integral membrane form acting as an ion channel. The soluble form is structurally related to the glutathione-S-transferase family, and CLIC can covalently bind glutathione via an active site cysteine. We report approximately 0.6 s of molecular dynamics simulations, encompassing the three possible ligand-bound states of CLIC1, using the structure of GSH-bound human CLIC1. Noncovalently bound GSH was rapidly released from the protein, whereas the covalently ligand-bound protein remained close to the starting structure over 0.25 s of simulation. In the unliganded state, conformational changes in the vicinity of the glutathione-binding site resulted in reduced reactivity of the active site thiol. Elastic network analysis indicated that the changes in the unliganded state are intrinsic to the protein architecture and likely represent functional transitions. Overall, our results are consistent with a model of CLIC function in which covalent binding of glutathione does not occur spontaneously but requires interaction with another protein to stabilise the GSH binding site and/or transfer of the ligand. The results do not indicate how CLIC1 undergoes a radical conformational change to form a transmembrane chloride channel but further elucidate the mechanism by which CLICs are redox controlled.

Details

ISSN :
23146141 and 23146133
Volume :
2013
Database :
OpenAIRE
Journal :
BioMed Research International
Accession number :
edsair.doi.dedup.....a7601b3dd5e5c04f00fee0fb07d4b347
Full Text :
https://doi.org/10.1155/2013/170586