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

Lilia Leisle, Kin Lam, Sepehr Dehghani-Ghahnaviyeh, Eva Fortea, Jason D. Galpin, Christopher A. Ahern, Emad Tajkhorshid and Alessio Accardi ()
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Lilia Leisle: Weill Cornell Medical College
Kin Lam: University of Illinois at Urbana-Champaign
Sepehr Dehghani-Ghahnaviyeh: University of Illinois at Urbana-Champaign
Eva Fortea: Weill Cornell Medical College
Jason D. Galpin: University of Iowa
Christopher A. Ahern: University of Iowa
Emad Tajkhorshid: University of Illinois at Urbana-Champaign
Alessio Accardi: Weill Cornell Medical College

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Chloride homeostasis is regulated in all cellular compartments. CLC-type channels selectively transport Cl− across biological membranes. It is proposed that side-chains of pore-lining residues determine Cl− selectivity in CLC-type channels, but their spatial orientation and contributions to selectivity are not conserved. This suggests a possible role for mainchain amides in selectivity. We use nonsense suppression to insert α-hydroxy acids at pore-lining positions in two CLC-type channels, CLC-0 and bCLC-k, thus exchanging peptide-bond amides with ester-bond oxygens which are incapable of hydrogen-bonding. Backbone substitutions functionally degrade inter-anion discrimination in a site-specific manner. The presence of a pore-occupying glutamate side chain modulates these effects. Molecular dynamics simulations show backbone amides determine ion energetics within the bCLC-k pore and how insertion of an α-hydroxy acid alters selectivity. We propose that backbone-ion interactions are determinants of Cl− specificity in CLC channels in a mechanism reminiscent of that described for K+ channels.

Date: 2022
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DOI: 10.1038/s41467-022-35279-1

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