Cryo-EM structures and functional characterization of murine Slc26a9 reveal mechanism of uncoupled chloride transport

The epithelial anion transporter SLC26A9 contributes to airway surface hydration and gastric acid production. Colocalizing with CFTR, SLC26A9 has been proposed as a target for the treatment of cystic fibrosis. To provide molecular details of its transport mechanism, we present cryo-EM structures and...

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Main Authors: Justin D Walter, Marta Sawicka, Raimund Dutzler
Format: Article
Language:English
Published: eLife Sciences Publications Ltd 2019-07-01
Series:eLife
Subjects:
Online Access:https://elifesciences.org/articles/46986
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author Justin D Walter
Marta Sawicka
Raimund Dutzler
author_facet Justin D Walter
Marta Sawicka
Raimund Dutzler
author_sort Justin D Walter
collection DOAJ
description The epithelial anion transporter SLC26A9 contributes to airway surface hydration and gastric acid production. Colocalizing with CFTR, SLC26A9 has been proposed as a target for the treatment of cystic fibrosis. To provide molecular details of its transport mechanism, we present cryo-EM structures and a functional characterization of murine Slc26a9. These structures define the general architecture of eukaryotic SLC26 family members and reveal an unusual mode of oligomerization which relies predominantly on the cytosolic STAS domain. Our data illustrates conformational transitions of Slc26a9, supporting a rapid alternate-access mechanism which mediates uncoupled chloride transport with negligible bicarbonate or sulfate permeability. The characterization of structure-guided mutants illuminates the properties of the ion transport path, including a selective anion binding site located in the center of a mobile module within the transmembrane domain. This study thus provides a structural foundation for the understanding of the entire SLC26 family and potentially facilitates their therapeutic exploitation.
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spelling doaj.art-dbe2fb604f9d45c8a7fe11a823aff74f2022-12-22T02:04:58ZengeLife Sciences Publications LtdeLife2050-084X2019-07-01810.7554/eLife.46986Cryo-EM structures and functional characterization of murine Slc26a9 reveal mechanism of uncoupled chloride transportJustin D Walter0https://orcid.org/0000-0002-1492-3055Marta Sawicka1https://orcid.org/0000-0003-4589-4290Raimund Dutzler2https://orcid.org/0000-0002-2193-6129Department of Biochemistry, University of Zurich, Zurich, SwitzerlandDepartment of Biochemistry, University of Zurich, Zurich, SwitzerlandDepartment of Biochemistry, University of Zurich, Zurich, SwitzerlandThe epithelial anion transporter SLC26A9 contributes to airway surface hydration and gastric acid production. Colocalizing with CFTR, SLC26A9 has been proposed as a target for the treatment of cystic fibrosis. To provide molecular details of its transport mechanism, we present cryo-EM structures and a functional characterization of murine Slc26a9. These structures define the general architecture of eukaryotic SLC26 family members and reveal an unusual mode of oligomerization which relies predominantly on the cytosolic STAS domain. Our data illustrates conformational transitions of Slc26a9, supporting a rapid alternate-access mechanism which mediates uncoupled chloride transport with negligible bicarbonate or sulfate permeability. The characterization of structure-guided mutants illuminates the properties of the ion transport path, including a selective anion binding site located in the center of a mobile module within the transmembrane domain. This study thus provides a structural foundation for the understanding of the entire SLC26 family and potentially facilitates their therapeutic exploitation.https://elifesciences.org/articles/46986chloride transportalternate accesspatch clampcryo-EM
spellingShingle Justin D Walter
Marta Sawicka
Raimund Dutzler
Cryo-EM structures and functional characterization of murine Slc26a9 reveal mechanism of uncoupled chloride transport
eLife
chloride transport
alternate access
patch clamp
cryo-EM
title Cryo-EM structures and functional characterization of murine Slc26a9 reveal mechanism of uncoupled chloride transport
title_full Cryo-EM structures and functional characterization of murine Slc26a9 reveal mechanism of uncoupled chloride transport
title_fullStr Cryo-EM structures and functional characterization of murine Slc26a9 reveal mechanism of uncoupled chloride transport
title_full_unstemmed Cryo-EM structures and functional characterization of murine Slc26a9 reveal mechanism of uncoupled chloride transport
title_short Cryo-EM structures and functional characterization of murine Slc26a9 reveal mechanism of uncoupled chloride transport
title_sort cryo em structures and functional characterization of murine slc26a9 reveal mechanism of uncoupled chloride transport
topic chloride transport
alternate access
patch clamp
cryo-EM
url https://elifesciences.org/articles/46986
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AT martasawicka cryoemstructuresandfunctionalcharacterizationofmurineslc26a9revealmechanismofuncoupledchloridetransport
AT raimunddutzler cryoemstructuresandfunctionalcharacterizationofmurineslc26a9revealmechanismofuncoupledchloridetransport