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Integrating mass spectrometry with MD simulations reveals the role of lipids in Na+/H+ antiporters
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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Number of Authors: 112017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 13993Article in journal (Refereed) Published
Abstract [en]

Na+/H+ antiporters are found in all kingdoms of life and exhibit catalysis rates that are among the fastest of all known secondary- active transporters. Here we combine ion mobility mass spectrometry and molecular dynamics simulations to study the conformational stability and lipid- binding properties of the Na+/H+ exchanger NapA from Thermus thermophilus and compare this to the prototypical antiporter NhaA from Escherichia coli and the human homologue NHA2. We find that NapA and NHA2, but not NhaA, form stable dimers and do not selectively retain membrane lipids. By comparing wild- type NapA with engineered variants, we show that the unfolding of the protein in the gas phase involves the disruption of inter- domain contacts. Lipids around the domain interface protect the native fold in the gas phase by mediating contacts between the mobile protein segments. We speculate that elevator- type antiporters such as NapA, and likely NHA2, use a subset of annular lipids as structural support to facilitate large- scale conformational changes within the membrane.

Place, publisher, year, edition, pages
2017. Vol. 8, article id 13993
National Category
Biological Sciences
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:su:diva-139365DOI: 10.1038/ncomms13993ISI: 000391641800001OAI: oai:DiVA.org:su-139365DiVA, id: diva2:1072724
Available from: 2017-02-08 Created: 2017-02-06 Last updated: 2017-11-29Bibliographically 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. p. 47
Keywords
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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