Structure and mechanism of the cation-chloride cotransporter NKCC1.

Nature
Thomas A ChewLiang Feng

Abstract

Cation-chloride cotransporters (CCCs) mediate the electroneutral transport of chloride, potassium and/or sodium across the membrane. They have critical roles in regulating cell volume, controlling ion absorption and secretion across epithelia, and maintaining intracellular chloride homeostasis. These transporters are primary targets for some of the most commonly prescribed drugs. Here we determined the cryo-electron microscopy structure of the Na-K-Cl cotransporter NKCC1, an extensively studied member of the CCC family, from Danio rerio. The structure defines the architecture of this protein family and reveals how cytosolic and transmembrane domains are strategically positioned for communication. Structural analyses, functional characterizations and computational studies reveal the ion-translocation pathway, ion-binding sites and key residues for transport activity. These results provide insights into ion selectivity, coupling and translocation, and establish a framework for understanding the physiological functions of CCCs and interpreting disease-related mutations.

References

Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Sep 26, 1997·The Journal of Biological Chemistry·P Isenring, B Forbush
Jan 5, 2000·Physiological Reviews·J M Russell
Jun 9, 2000·Annual Review of Physiology·M Haas, B Forbush
Apr 27, 2002·Acta Crystallographica. Section D, Biological Crystallography·Marjorie M Harding
Jul 30, 2002·The Journal of Biological Chemistry·Andreas W FlemmerBiff Forbush
Dec 20, 2002·JAMA : the Journal of the American Medical Association·UNKNOWN ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatm
Mar 22, 2003·Science·Raimund DutzlerRoderick MacKinnon
May 26, 2005·Bioinformatics·Liskin Swint-Kruse, Curties S Brown
Apr 4, 2006·Advances in Chronic Kidney Disease·Nine V A M Knoers
Jun 28, 2007·Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology·Kenneth B E GagnonEric Delpire
May 22, 2009·Nature·Harini KrishnamurthyEric Gouaux
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Vincent B ChenDavid C Richardson
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
May 26, 2010·The Journal of Physical Chemistry. B·Jeffery B KlaudaRichard W Pastor
Jun 10, 2010·Expert Review of Cardiovascular Therapy·Julio D Duarte, Rhonda M Cooper-DeHoff
Nov 22, 2011·Seminars in Nephrology·Robert W Schrier
Nov 29, 2011·The Journal of Biological Chemistry·Michelle Y Monette, Biff Forbush
Jun 23, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Zeng-You YeHui-Lin Pan
Jul 21, 2012·Nature Protocols·Morten KällbergJinbo Xu
Sep 25, 2012·Journal of Structural Biology·Sjors H W Scheres
Jan 18, 2013·American Journal of Physiology. Cell Physiology·Kenneth B Gagnon, Eric Delpire
Mar 20, 2013·Molecular Aspects of Medicine·Juan Pablo ArroyoGerardo Gamba
Jul 23, 2013·Journal of Structural Biology·Dmitry LyumkisNikolaus Grigorieff
Oct 8, 2013·Pflügers Archiv : European journal of physiology·Nicolas Markadieu, Eric Delpire
Sep 23, 2014·Nature Reviews. Neuroscience·Kai KailaJuha Voipio
Feb 5, 2015·Biotechnology Journal·Eric KowarzRolf Marschalek
Feb 6, 2015·Frontiers in Cellular Neuroscience·Anna-Maria Hartmann, Hans Gerd Nothwang
Apr 7, 2015·Acta Biochimica Et Biophysica Sinica·Linghong WangXiulan Su
Aug 19, 2015·Journal of Structural Biology·Alexis Rohou, Nikolaus Grigorieff

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Citations

Nov 21, 2019·American Journal of Physiology. Cell Physiology·Eric Delpire, Jiangtao Guo
May 5, 2020·The Journal of Cell Biology·Katy L H Marshall-PhelpsDavid A Lyons
Jul 14, 2020·Brain : a Journal of Neurology·Alisdair McNeillEric Delpire
Sep 12, 2019·Nature Reviews. Nephrology·Alexandre P Garneau, Paul Isenring
Aug 29, 2020·Acta Pharmacologica Sinica·Zheng-Wei LuoHong-Shuo Sun
Apr 15, 2020·ELife·Michelle S ReidStephen Graf Brohawn
Dec 15, 2020·ELife·Dana M TalsnessClement Y Chow
Dec 29, 2020·American Journal of Physiology. Cell Physiology·Eric Delpire
Dec 4, 2020·International Journal of Molecular Sciences·Katie AndrewsJinwei Zhang
Dec 9, 2020·International Journal of Molecular Sciences·Tomas Koltai
Dec 22, 2020·Function·Rainelli KoumangoyeEric Delpire
Feb 19, 2021·Communications Biology·Sensen ZhangMaojun Yang
Mar 1, 2021·Trends in Neurosciences·Mari A VirtanenKai Kaila
May 6, 2021·Physiological Reviews·Martin Kaag RasmussenMaiken Nedergaard
May 6, 2021·Physiological Reviews·Ole H PetersenShuang Peng
May 26, 2021·The EMBO Journal·Rasmus Kock FlygaardPoul Nissen
May 22, 2021·The Journal of Biological Chemistry·Anna-Maria HartmannHans Gerd Nothwang
May 23, 2021·Journal of Molecular Biology·Thomas A ChewLiang Feng
Jul 24, 2021·Nature Communications·Lie WangMing Zhou
Jul 3, 2021·Journal of Chemical Information and Modeling·Pavel Janoš, Alessandra Magistrato
Aug 8, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Vertika GautamVannajan Sanghiran Lee
Aug 14, 2021·Nature Communications·Anastasiia SukalskaiaRaimund Dutzler
Sep 25, 2021·Organic & Biomolecular Chemistry·Jun ZhuDe-Xian Wang

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Methods Mentioned

BETA
electron microscopy
FRET
gel filtration
fluorescence imaging
electron

Software Mentioned

Phenix
RELION
CTFFIND4
PROPKA
_ analyse
MotionCor2
PMEMD
Molprobity
VMD
relion3

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