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The role of interfacial lipids in stabilizing membrane protein oligomers
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Gupta, Kallol, Donlan, Joseph A. C., Hopper, Jonathan T. S., Uzdavinys, Povilas, Landreh, Michael, Struwe, Weston B., Drew, David, Baldwin, Andrew J., Stansfeld, Phillip J. and Robinson, Carol V. (2017) The role of interfacial lipids in stabilizing membrane protein oligomers. Nature, 541 (7637). pp. 421-424. doi:10.1038/nature20820
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WRAP-role-interfacial-lipids-stabilising-membrane-protein-oligomers-Stansfeld-2017.pdf - Accepted Version - Requires a PDF viewer. Download (3604Kb) | Preview |
Official URL: http://dx.doi.org/10.1038/nature20820
Abstract
Oligomerization of membrane proteins in response to lipid binding has a critical role in many cell-signalling pathways1 but is often difficult to define2 or predict3. Here we report the development of a mass spectrometry platform to determine simultaneously the presence of interfacial lipids and oligomeric stability and to uncover how lipids act as key regulators of membrane-protein association. Evaluation of oligomeric strength for a dataset of 125 α-helical oligomeric membrane proteins reveals an absence of interfacial lipids in the mass spectra of 12 membrane proteins with high oligomeric stability. For the bacterial homologue of the eukaryotic biogenic transporters (LeuT4, one of the proteins with the lowest oligomeric stability), we found a precise cohort of lipids within the dimer interface. Delipidation, mutation of lipid-binding sites or expression in cardiolipin-deficient Escherichia coli abrogated dimer formation. Molecular dynamics simulation revealed that cardiolipin acts as a bidentate ligand, bridging across subunits. Subsequently, we show that for the Vibrio splendidus sugar transporter SemiSWEET5, another protein with low oligomeric stability, cardiolipin shifts the equilibrium from monomer to functional dimer. We hypothesized that lipids are essential for dimerization of the Na+/H+ antiporter NhaA from E. coli, which has the lowest oligomeric strength, but not for the substantially more stable homologous Thermus thermophilus protein NapA. We found that lipid binding is obligatory for dimerization of NhaA, whereas NapA has adapted to form an interface that is stable without lipids. Overall, by correlating interfacial strength with the presence of interfacial lipids, we provide a rationale for understanding the role of lipids in both transient and stable interactions within a range of α-helical membrane proteins, including G-protein-coupled receptors.
| Item Type: | Journal Article | |||||||||||||||||||||
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| Subjects: | Q Science > QD Chemistry Q Science > QP Physiology |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | |||||||||||||||||||||
| Library of Congress Subject Headings (LCSH): | Lipids, Membrane proteins, Oligomers | |||||||||||||||||||||
| Journal or Publication Title: | Nature | |||||||||||||||||||||
| Publisher: | Nature Publishing | |||||||||||||||||||||
| ISSN: | 0028-0836 | |||||||||||||||||||||
| Official Date: | 11 January 2017 | |||||||||||||||||||||
| Dates: |
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| Volume: | 541 | |||||||||||||||||||||
| Number: | 7637 | |||||||||||||||||||||
| Page Range: | pp. 421-424 | |||||||||||||||||||||
| DOI: | 10.1038/nature20820 | |||||||||||||||||||||
| Status: | Peer Reviewed | |||||||||||||||||||||
| Publication Status: | Published | |||||||||||||||||||||
| Access rights to Published version: | Restricted or Subscription Access | |||||||||||||||||||||
| RIOXX Funder/Project Grant: |
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