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

Michael Landreh, Erik G. Marklund, Povilas Uzdavinys, Matteo T. Degiacomi, Mathieu Coincon, Joseph Gault, Kallol Gupta, Idlir Liko, Justin L. P. Benesch, David Drew () and Carol V. Robinson ()
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Michael Landreh: Physical & Theoretical Chemistry Laboratory, University of Oxford
Erik G. Marklund: Physical & Theoretical Chemistry Laboratory, University of Oxford
Povilas Uzdavinys: Centre for Biomembrane Research, Stockholm University
Matteo T. Degiacomi: Physical & Theoretical Chemistry Laboratory, University of Oxford
Mathieu Coincon: Centre for Biomembrane Research, Stockholm University
Joseph Gault: Physical & Theoretical Chemistry Laboratory, University of Oxford
Kallol Gupta: Physical & Theoretical Chemistry Laboratory, University of Oxford
Idlir Liko: Physical & Theoretical Chemistry Laboratory, University of Oxford
Justin L. P. Benesch: Physical & Theoretical Chemistry Laboratory, University of Oxford
David Drew: Centre for Biomembrane Research, Stockholm University
Carol V. Robinson: Physical & Theoretical Chemistry Laboratory, University of Oxford

Nature Communications, 2017, vol. 8, issue 1, 1-9

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms13993

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