Challenging accepted ion channel biology: p64 and the CLIC family of putative intracellular anion channel proteins (Review)

Parchorin, p64 and the related chloride intracellular channel (CLIC) proteins are widely expressed in multicellular organisms and have emerged as candidates for novel, auto-inserting, self-assembling intracellular anion channels involved in a wide variety of fundamental cellular events including regulated secretion, cell division and apoptosis. Although the mammalian phosphoproteins p64 and parchorin (49 and 65K, respectively) have only been indirectly implicated in anion channel activity, two CLIC proteins (CLIC1 and CLIC4, 27 and 29K, respectively) appear to be essential molecular components of anion channels, and CLIC1 can form anion channels in planar lipid bilayers in the absence of other cellular proteins. However, these putative ion channel proteins are controversial because they exist in both soluble and membrane forms, with at least one transmembrane domain. Even more surprisingly, soluble CLICs share the same glutaredoxin fold as soluble omega class glutathione-S-transferases. Working out how these ubiquitous, soluble proteins unfold, insert into membranes and then refold to form integral membrane proteins, and how cells control this potentially dangerous process and make use of the associated ion channels, are challenging prospects. Critical to this future work is the need for better characterization of membrane topology, careful functional analysis of reconstituted and native channels, including their conductances and selectivities, and detailed structure/function studies including targeted mutagenesis to investigate the structure of the putative pore, the role of protein phosphorylation and the role of conserved cysteine residues.