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A two-domain elevator mechanism for sodium/proton antiport
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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2013 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 501, no 7468, 573-577 p.Article in journal (Refereed) Published
Abstract [en]

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 targets(2). The best understood model system for Na+/H+ antiport is NhaA from Escherichia coli(1,3), for which both electron microscopy and crystal structures are available(4-6). 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 protein(1,4). Likemany 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 occur(7). The only reported NhaA crystal structure so far is of the low pH inactivated form(4). Here we describe the active-state structure of a Na+/H+ antiporter, NapA from Thermus thermophilus, at 3 angstrom resolution, solved from crystals grown at pH7.8. 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 binding(1,8,9) directly, a role supported hereby molecular dynamics simulations. To alternate access to this ion-binding site, however, requires a surprisingly large rotation of the core domain, some 20 degrees against the dimerization interface. We conclude that despite their fast transport rates of up to 1,500 ions per second(3), Na+/H+ antiporters operate by a two-domain rocking bundle model, revealing themes relevant to secondary-active transporters in general.

Place, publisher, year, edition, pages
2013. Vol. 501, no 7468, 573-577 p.
National Category
Biological Sciences
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:su:diva-95768DOI: 10.1038/nature12484ISI: 000324826300064OAI: oai:DiVA.org:su-95768DiVA: diva2:661763
Note

AuthorCount:10;

Available from: 2013-11-04 Created: 2013-11-04 Last updated: 2017-09-22Bibliographically approved
In thesis
1. Establishing the molecular mechanism of sodium/proton exchangers
Open this publication in new window or tab >>Establishing the molecular mechanism of sodium/proton exchangers
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Sodium/proton exchangers are ubiquitous secondary active transporters that can be found in all kingdoms of life. These proteins facilitate the transport of protons in exchange for sodium ions to help regulate internal pH, sodium levels, and cell volume. Na+/H+ exchangers belong to the SLC9 family and are involved in many physiological processes including cell proliferation, cell migration and vesicle trafficking. Dysfunction of these proteins has been linked to physiological disorders, such as hypertension, heart failure, epilepsy and diabetes.

The goal of my thesis is to establish the molecular basis of ion exchange in Na+/H+ exchangers. By establishing how they bind and catalyse the movement of ions across the membrane, we hope we can better understand their role in human physiology.

In my thesis, I will first present an overview of Na+/H+ exchangers and their molecular mechanism of ion translocation as was currently understood by structural and functional studies when I started my PhD studies. I will outline our important contributions to this field, which were to (i) obtain the first atomic structures of the same Na+/H+ exchanger (NapA) in two major alternating conformations, (ii) show how a transmembrane embedded lysine residue is essential for carrying out electrogenic transport, and (iii) isolate and recorde the first kinetic data of a mammalian Na+/H+ exchanger (NHA2) in an isolated liposome reconstitution system.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2017. 47 p.
Keyword
membrane protein, secondary active transporters, sodium/proton exchangers, proton transport, structure, energetics
National Category
Biochemistry and Molecular Biology Structural Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-147333 (URN)978-91-7649-964-1 (ISBN)978-91-7649-965-8 (ISBN)
Public defence
2017-11-14, William-Olssonsalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 10:00 (English)
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Available from: 2017-10-20 Created: 2017-09-22 Last updated: 2017-10-20Bibliographically approved

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