Backbone amides are key determinants of Cl selectivity in CLC ion channels

Author:

Leisle Lilia,Lam Kin,Dehghani-Ghahnaviyeh Sepehr,Fortea Eva,Galpin Jason,Ahern Christopher A.,Tajkhorshid EmadORCID,Accardi AlessioORCID

Abstract

AbstractChloride homeostasis is tightly regulated in cellular compartments by dedicated channels and transporters. Whereas CLC-type channels select for Cl over other anions, all other ‘chloride’ channels are indiscriminate in their anionic permeability. Pore-lining side chains are thought to determine Cl selectivity in CLC channels. However, orientation and functional roles of these side chains is not conserved among CLCs. All CLC pores are lined by backbone amides in a conserved structural arrangement, suggesting a role of mainchain groups in selectivity. We replaced pore-lining residues in the CLC-0 and bCLC-k channels with their respective α-hydroxy acid counterparts using nonsense suppression method. This exchanges peptide-bond amides with ester-bond oxygens, incapable of hydrogen-bonding with permeating anions. Backbone substitutions functionally degrade inter-anion discrimination in a site-specific manner. These effects depend on the presence of a glutamate side chain that competes with ions permeating through the pore. Molecular dynamics simulations show that ion energetics within the bCLC-k pore are primarily determined by interactions with backbone amides. Insertion of an α-hydroxy acid significantly alters ion selectivity and global pore hydration. We propose that backbone amides are conserved determinants of Cl specificity in CLC channels in a mechanism reminiscent of that described for K+ channels.

Publisher

Cold Spring Harbor Laboratory

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