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, Alessio Accardi

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number7508
JournalNature communications
Issue number1
StatePublished - Dec 2022

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy


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