Native Mass Spectrometry of Membrane Protein Lipid and Ligand Complexes Using de novo Designed WRAP Domains

ABSTRACT Membrane proteins engage in dynamic transient interactions with surrounding lipids along with their substrates. Capturing these concomitant contacts often remains a challenging problem. Here, we demonstrate that generative deep learning-designed WRAP domains can preserve weak interactions of membrane protein complexes in native mass spectrometry. Using WRAP-fused GlpG, AqpM, and OmpA as model systems, we show that lipid interactions can be retained and characterized without detergent micelles. We use the approach to show that WRAP-OmpA selectively binds phosphatidylethanolamine lipids within cavities formed at the protein–WRAP interface, while simultaneously accommodating weak chitobiose ligand binding. These findings establish WRAPs as versatile vehicles to probe ligand and lipid interactions of membrane proteins.

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Publication Details

Journal
Journal of the American Chemical Society
Published
2026-11-07
DOI
https://doi.org/10.1021/jacs.6c15293
Primary Topic
Mass Spectrometry Techniques and Applications
Type
article
Field-Weighted Citation Impact
0.00

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article

Native Mass Spectrometry of Membrane Protein Lipid and Ligand Complexes Using de novo Designed WRAP Domains

Ljubica Mihaljević, David A. Baker, Erik G. Marklund, Phillip J. Stansfeld et al.
1 links
Journal of the American Chemical Society
Mass Spectrometry Techniques and Applications
article

Native Mass Spectrometry of Membrane Protein Lipid and Ligand Complexes Using de novo Designed WRAP Domains

Ljubica Mihaljević, David A. Baker, Erik G. Marklund, Phillip J. Stansfeld, Michael Landreh, Barbara Abreu, Surabhi Kokane, Alexander Stevens, Stijn de Schepper
article en

Abstract

ABSTRACT Membrane proteins engage in dynamic transient interactions with surrounding lipids along with their substrates. Capturing these concomitant contacts often remains a challenging problem. Here, we demonstrate that generative deep learning-designed WRAP domains can preserve weak interactions of membrane protein complexes in native mass spectrometry. Using WRAP-fused GlpG, AqpM, and OmpA as model systems, we show that lipid interactions can be retained and characterized without detergent micelles. We use the approach to show that WRAP-OmpA selectively binds phosphatidylethanolamine lipids within cavities formed at the protein–WRAP interface, while simultaneously accommodating weak chitobiose ligand binding. These findings establish WRAPs as versatile vehicles to probe ligand and lipid interactions of membrane proteins.

Journal of the American Chemical Society
Uppsala University (SE), University of Washington (US), Karolinska Institutet (SE), University of Warwick (GB)
European Commission, Cancerfonden, Svenska Sällskapet för Medicinsk Forskning, Karolinska Institutet, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, H2020 Marie Skłodowska-Curie Actions
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Mass Spectrometry Techniques and Applications
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Native Mass Spectrometry of Membrane Protein Lipid and Ligand Complexes Using de novo Designed WRAP Domains — Ljubica Mihaljević, David A. Baker, et al. · Journal of the American Chemical Society (2026) | TGRS Research Map | TGRS