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

Author

Listed:
  • Michael Landreh

    (Physical & Theoretical Chemistry Laboratory, University of Oxford)

  • Erik G. Marklund

    (Physical & Theoretical Chemistry Laboratory, University of Oxford
    Uppsala University)

  • 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)

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.

Suggested Citation

  • Michael Landreh & Erik G. Marklund & Povilas Uzdavinys & Matteo T. Degiacomi & Mathieu Coincon & Joseph Gault & Kallol Gupta & Idlir Liko & Justin L. P. Benesch & David Drew & Carol V. Robinson, 2017. "Integrating mass spectrometry with MD simulations reveals the role of lipids in Na+/H+ antiporters," Nature Communications, Nature, vol. 8(1), pages 1-9, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms13993
    DOI: 10.1038/ncomms13993
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    Cited by:

    1. James S. Davies & Michael J. Currie & Rachel A. North & Mariafrancesca Scalise & Joshua D. Wright & Jack M. Copping & Daniela M. Remus & Ashutosh Gulati & Dustin R. Morado & Sam A. Jamieson & Michael , 2023. "Structure and mechanism of a tripartite ATP-independent periplasmic TRAP transporter," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Iven Winkelmann & Povilas Uzdavinys & Ian M. Kenney & Joseph Brock & Pascal F. Meier & Lina-Marie Wagner & Florian Gabriel & Sukkyeong Jung & Rei Matsuoka & Christoph Ballmoos & Oliver Beckstein & Dav, 2022. "Crystal structure of the Na+/H+ antiporter NhaA at active pH reveals the mechanistic basis for pH sensing," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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