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A two-domain elevator mechanism for sodium/proton antiport
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Lee, Chiara, Kang, Hae Joo, von Ballmoos, Christoph, Newstead, Simon, Uzdavinys, Povilas, Dotson, David L., Iwata, So, Beckstein, Oliver, Cameron, Alexander and Drew, David (2013) A two-domain elevator mechanism for sodium/proton antiport. Nature, Volume 501 (Number 7468). pp. 573-577. doi:10.1038/nature12484 ISSN 0028-0836.
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Official URL: http://dx.doi.org/10.1038/nature12484
Abstract
Sodium/proton (Na+/H+) antiporters, located at the plasma membrane in every cell, are vital for cell homeostasis1. In humans, their dysfunction has been linked to diseases, such as hypertension, heart failure and epilepsy, and they are well-established drug targets2. The best understood model system for Na+/H+ antiport is NhaA from Escherichia coli1, 3, for which both electron microscopy and crystal structures are available4, 5, 6. NhaA is made up of two distinct domains: a core domain and a dimerization domain. In the NhaA crystal structure a cavity is located between the two domains, providing access to the ion-binding site from the inward-facing surface of the protein1, 4. Like many Na+/H+ antiporters, the activity of NhaA is regulated by pH, only becoming active above pH 6.5, at which point a conformational change is thought to occur7. The only reported NhaA crystal structure so far is of the low pH inactivated form4. Here we describe the active-state structure of a Na+/H+ antiporter, NapA from Thermus thermophilus, at 3 Å resolution, solved from crystals grown at pH 7.8. In the NapA structure, the core and dimerization domains are in different positions to those seen in NhaA, and a negatively charged cavity has now opened to the outside. The extracellular cavity allows access to a strictly conserved aspartate residue thought to coordinate ion binding1, 8, 9 directly, a role supported here by molecular dynamics simulations. To alternate access to this ion-binding site, however, requires a surprisingly large rotation of the core domain, some 20° against the dimerization interface. We conclude that despite their fast transport rates of up to 1,500 ions per second3, Na+/H+ antiporters operate by a two-domain rocking bundle model, revealing themes relevant to secondary-active transporters in general.
Item Type: | Journal Article | ||||
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Subjects: | Q Science > QC Physics Q Science > QD Chemistry |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||
Library of Congress Subject Headings (LCSH): | Homeostasis , Sodium, Hydrogen-ion concentration, Cytochemistry , Cytology | ||||
Journal or Publication Title: | Nature | ||||
Publisher: | Nature Publishing | ||||
ISSN: | 0028-0836 | ||||
Official Date: | 26 September 2013 | ||||
Dates: |
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Volume: | Volume 501 | ||||
Number: | Number 7468 | ||||
Page Range: | pp. 573-577 | ||||
DOI: | 10.1038/nature12484 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access | ||||
Date of first compliant deposit: | 25 December 2015 | ||||
Date of first compliant Open Access: | 25 December 2015 | ||||
Funder: | Medical Research Council (Great Britain) (MRC), Sweden. Vetenskapsrådet [Research Council], Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Wellcome Trust (London, England), Swedish Foundation for Strategic Research, Extreme Science and Engineering Discovery Environment (XSEDE), International Human Frontier Science Program Organization, Royal Society (Great Britain) | ||||
Grant number: | G0900990 (MRC) ; BB/G02325/1 (BBSRC) ; 062164/Z/00/Z (WT) ; TG-MCB120151 (XSEDE) ; |
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