Molecular mechanism of exchange coupling in CLC chloride/proton antiporters.

ABSTRACT: The ubiquitous CLC membrane transporters are unique in their ability to exchange anions for cations. Despite extensive study, there is no mechanistic model that fully explains their 2:1 Cl^‒/H⁺ stoichiometric exchange mechanism. Here, we provide such a model. Using differential hydrogen-deuterium exchange mass spectrometry, cryo-EM structure determination, and molecular dynamics simulations, we uncovered conformational dynamics in CLC-ec1, a bacterial CLC homolog that has served as a paradigm for this family of transporters. Simulations based on a cryo-EM structure at pH 3 revealed critical steps in the transport mechanism, including release of Cl^‒ ions to the extracellular side, opening of the inner gate, and water wires that facilitate H⁺ transp

SUBMITTER: Aydin D 

PROVIDER: S-EPMC12873427 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature