A CLC-EC1 mutant reveals global conformational change and suggests a unifying mechanism for the CLC CL /H+ transport cycle

Tanmay S. Chavan, Ricky C. Cheng, Tao Jiang, Irimpan I. Mathews, Richard A. Stein, Antoine Koehl, Hassane S. McHaourab, Emad Tajkhorshid, Merritt Maduke

Research output: Contribution to journalArticle

Abstract

Among coupled exchangers, CLCs uniquely catalyze the exchange of oppositely charged ions (Cl for H+). Transport-cycle models to describe and explain this unusual mechanism have been proposed based on known CLC structures. While the proposed models harmonize with many experimental findings, gaps and inconsistencies in our understanding have remained. One limitation has been that global conformational change – which occurs in all conventional transporter mechanisms – has not been observed in any high-resolution structure. Here, we describe the 2.6 Å structure of a CLC mutant designed to mimic the fully H+-loaded transporter. This structure reveals a global conformational change to improve accessibility for the Cl substrate from the extracellular side and new conformations for two key glutamate residues. Together with DEER measurements, MD simulations, and functional studies, this new structure `provides evidence for a unified model of H+ /Cl transport that reconciles existing data on all CLC-type proteins.

Original languageEnglish (US)
Article numbere53479
JournaleLife
Volume9
DOIs
StatePublished - Apr 2020

Keywords

  • Antiporter
  • Crystallization
  • DEER spectroscopy
  • MD simulations
  • Membrane exchanger

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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    Chavan, T. S., Cheng, R. C., Jiang, T., Mathews, I. I., Stein, R. A., Koehl, A., McHaourab, H. S., Tajkhorshid, E., & Maduke, M. (2020). A CLC-EC1 mutant reveals global conformational change and suggests a unifying mechanism for the CLC CL /H+ transport cycle. eLife, 9, [e53479]. https://doi.org/10.7554/eLife.53479