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Integrating mass spectrometry with MD simulations reveals the role of lipids in Na+/H+ antiporters.

Landreh, M. and Marklund, E.G. and Uzdavinys, P. and Degiacomi, M.T. and Coincon, M. and Gault, J. and Gupta, K. and Liko, I. and Benesch, J.L.P. and Drew, D. and Robinson, C.V. (2017) 'Integrating mass spectrometry with MD simulations reveals the role of lipids in Na+/H+ antiporters.', Nature communications., 8 . p. 13993.

Abstract

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.

Item Type:Article
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Status:Peer-reviewed
Publisher Web site:https://doi.org/10.1038/ncomms13993
Publisher statement:This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Date accepted:18 November 2016
Date deposited:02 August 2017
Date of first online publication:10 January 2017
Date first made open access:02 August 2017

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