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

doi:10.1038/s41467-022-35279-1

Back

Journal article

Open access

Peer reviewed

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

Nature communications, Vol.13(1), p.7508

12/06/2022

DOI: 10.1038/s41467-022-35279-1

PMCID: PMC9726985

PMID: 36473856

Files and links (1)

url

https://doi.org/10.1038/s41467-022-35279-1View

Published (Version of record) Open Access

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.

Details

Title: Subtitle: Backbone amides are determinants of Cl - selectivity in CLC ion channels
Creators: Lilia Leisle - Weill Cornell Medicine
Kin Lam - University of Illinois Urbana-Champaign
Sepehr Dehghani-Ghahnaviyeh - University of Illinois Urbana-Champaign
Eva Fortea - Weill Cornell Medicine
Jason D Galpin - University of Iowa
Christopher A Ahern - University of Iowa
Emad Tajkhorshid - University of Illinois Urbana-Champaign
Alessio Accardi - Weill Cornell Medicine
Resource Type: Journal article
Publication Details: Nature communications, Vol.13(1), p.7508
DOI: 10.1038/s41467-022-35279-1
PMID: 36473856
PMCID: PMC9726985
NLM abbreviation: Nat Commun
eISSN: 2041-1723
Grant note: MCA06N060 / NSF | BIO | Division of Biological Infrastructure (DBI) OCI-0725070 / National Centre for Supercomputing Applications (NCSA) GM123455 / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) R24 NS104617 / NINDS NIH HHS P41-GM104601 / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) GM106569 / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) GM128420 / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) ACI-1238993 / National Centre for Supercomputing Applications (NCSA)
Language: English
Date published: 12/06/2022
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute
Record Identifier: 9984322761402771

Metrics

35 Record Views

See more details