A CLC-ec1 mutant reveals global conformational change and suggests a unifying mechanism for the CLC Cl–/H+ transport cycle
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.
- Authors:
-
[1];
[2];
[1]
- Department of Molecular & Cellular Physiology, Stanford University School of Medicine, Stanford, United States
- NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, Department of Biochemistry, Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, United States
- Stanford Synchrotron Radiation Lightsource, Stanford University, Menlo Park, United States
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, United States
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division
- OSTI Identifier:
- 1615422
- Alternate Identifier(s):
- OSTI ID: 1615423; OSTI ID: 1816262
- Grant/Contract Number:
- AC02-06CH11357
- Resource Type:
- Published Article
- Journal Name:
- eLife
- Additional Journal Information:
- Journal Name: eLife Journal Volume: 9; Journal ID: ISSN 2050-084X
- Publisher:
- eLife Sciences Publications, Ltd.
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Chavan, Tanmay S., Cheng, Ricky C., Jiang, Tao, Mathews, Irimpan I., Stein, Richard A., Koehl, Antoine, Mchaourab, Hassane S., Tajkhorshid, Emad, and Maduke, Merritt. A CLC-ec1 mutant reveals global conformational change and suggests a unifying mechanism for the CLC Cl–/H+ transport cycle. United States: N. p., 2020.
Web. doi:10.7554/eLife.53479.
Chavan, Tanmay S., Cheng, Ricky C., Jiang, Tao, Mathews, Irimpan I., Stein, Richard A., Koehl, Antoine, Mchaourab, Hassane S., Tajkhorshid, Emad, & Maduke, Merritt. A CLC-ec1 mutant reveals global conformational change and suggests a unifying mechanism for the CLC Cl–/H+ transport cycle. United States. https://doi.org/10.7554/eLife.53479
Chavan, Tanmay S., Cheng, Ricky C., Jiang, Tao, Mathews, Irimpan I., Stein, Richard A., Koehl, Antoine, Mchaourab, Hassane S., Tajkhorshid, Emad, and Maduke, Merritt. Mon .
"A CLC-ec1 mutant reveals global conformational change and suggests a unifying mechanism for the CLC Cl–/H+ transport cycle". United States. https://doi.org/10.7554/eLife.53479.
@article{osti_1615422,
title = {A CLC-ec1 mutant reveals global conformational change and suggests a unifying mechanism for the CLC Cl–/H+ transport cycle},
author = {Chavan, Tanmay S. and Cheng, Ricky C. and Jiang, Tao and Mathews, Irimpan I. and Stein, Richard A. and Koehl, Antoine and Mchaourab, Hassane S. and Tajkhorshid, Emad and Maduke, Merritt},
abstractNote = {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.},
doi = {10.7554/eLife.53479},
journal = {eLife},
number = ,
volume = 9,
place = {United States},
year = {Mon Apr 20 00:00:00 EDT 2020},
month = {Mon Apr 20 00:00:00 EDT 2020}
}
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