Structural characterization of an intermediate reveals a unified mechanism for the CLC Cl−/H+ transport cycle
Tanmay S Chavan,
Ricky C Cheng,
Irimpan I Mathews,
Richard A Stein,
Hassane S. Mchaourab,
Posted 27 Nov 2019
bioRxiv DOI: 10.1101/857136 (published DOI: 10.7554/eLife.53479)
Posted 27 Nov 2019
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 many experimental findings, there have remained gaps and inconsistencies. 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 H+-loaded transporter. This structure reveals a global conformational change to a state that has improved accessibility for the Cl− substrate from the extracellular side and new conformations for two key glutamate residues. Based on this new structure, together with DEER measurements, MD simulations, and functional studies, we propose a unified model of the CLC transport mechanism that reconciles existing data on all CLC-type proteins.
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