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The role of interfacial lipids in stabilizing membrane protein oligomers


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.

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Figure 1: Plot of buried surface area and number of salt bridges for oligomeric α-helical membrane proteins and native mass spectra.
Figure 2: Schematic of the high-energy MS/MS platform, mass spectra and molecular dynamics simulations of the lipid-bound LeuT dimer.
Figure 3: Mass spectrum recorded for SemiSWEET and the effect of cardiolipin on the monomer–dimer equilibrium.
Figure 4: Comparison of mass spectra of NhaA with NapA and plot of transporter stabilities with assorted G-protein-coupled receptors.


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We thank K. Giles (Waters Corporation) and J. Benesch for development of the high-energy source and T. Allison, M. Degiacomi and J. Gault for many helpful discussions. The Robinson group is funded by a Wellcome Trust Investigator Award (104633/Z/14/Z), an ERC Advanced Grant ENABLE (641317) and an MRC programme grant (MR/N020413/1). K.G. is a research fellow of the Royal Commission for the Exhibition of 1851 and a Junior Research Fellow at St Catherine’s College, Oxford. J.A.C.D. is supported by an EPSRC studentship, held at the Life Sciences Interface Doctoral Training Centre. M.L. holds an ERC Marie Curie Career Development Fellowship and is a Junior Research Fellow at St Cross College, Oxford. D.D. acknowledges support from the EMBO Young Investigator Program, Vetenskapsrådet and the Knut and Alice Wallenberg foundation. A.J.B. acknowledges a BBSRC David Phillip’s Fellowship, BB/J014346/1. The authors are also grateful for plasmids from E. Gouaux (LeuT), W. Frommer and L. Feng (SemiSWEET).

Author information

Authors and Affiliations



K.G. and C.V.R. designed the experiments. K.G. and J.A.C.D. performed protein expression and MS experiments. J.T.S.H. performed the high-energy experiments with K.G. K.G. and M.L. performed MS experiments on NapA and NhaA. P.U. expressed and purified NhaA and NapA under the guidance of D.D. J.A.C.D. purified SemiSWEET with the help of W.B.S. P.J.S. carried out molecular dynamics simulations. A.J.B. and K.G. performed theoretical calculations to determine the oligomeric strength. K.G. and C.V.R wrote the manuscript with contributions from all authors.

Corresponding author

Correspondence to Carol V. Robinson.

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The authors declare no competing financial interests.

Additional information

Reviewer Information Nature thanks S. Bernèche, A. Lee and J. Whitelegge for their contribution to the peer review of this work.

Extended data figures and tables

Extended Data Figure 1 Mass spectra of LeuT recorded with increasing collision voltages and of a LeuT fusion protein construct.

a, Mass spectra of LeuT, liberated from octylglucoside micelles, (green/grey spheres, most abundant charge state highlighted in pale blue), show that the 7.4-kDa lipid adduct (blue/purple head groups) is retained throughout the trap collision energy range (white, blue arrow) of the mass spectrometer. b, Mass spectra of LeuT expressed as a fusion protein with eYFP (LeuT–eYFP yellow circles), liberated from octylglucoside micelles, show that the dimer is similarly associated with a 7.4-kDa adduct.

Extended Data Figure 2 Mass spectra of LeuT following incubation with delipidating detergents and E. coli polar lipids.

a, Mass spectrum of LeuT liberated from octylglucoside micelles (green head groups) shows low-abundance delipidated monomers (green spheres, 59.3 kDa) and high-abundance lipid-bound dimers (green/black spheres, 126.0 kDa). b, Mass spectrum of LeuT after incubation with neopentyl glycol (NG, orange head-groups) shows only delipidated monomers. c, Mass spectrum of LeuT in octylglucoside (OG), after incubation with neopentyl glycol, shows only delipidated monomers. d, Mass spectrum recorded after incubation of delipidated LeuT monomers, in octylglucoside, with E. coli polar lipids (blue/purple head-groups) shows delipidated monomers and lipid-bound dimers. e, Mass spectrum recorded after adding dilysocardiolipin (blue head-groups) to delipidated monomeric LeuT in octylglucoside (c) shows no dimerization in the presence of this lipid.

Extended Data Figure 3 High-energy MS/MS experiment of the 23+ charge state of dimeric LeuT, with the 7.4-kDa adduct, as a function of collision voltage.

Three satellite peaks represent the lipid-bound states arising through the dissociation of the monomer. The naked monomer is highlighted in blue, while the three satellite peaks are assigned to one phospholipid, one cardiolipin and three phospholipid-bound species (red, green and yellow, respectively). Under higher energy, only the cardiolipin-bound species remains, discounting the mathematical possibility of two phospholipid-bound species. Inset shows the isolated 23+ charge state of the lipid bound dimer. Presence of bound cardiolipin at a higher energy, over that of phospholipid, indicates a higher binding energy of cardiolipin over the latter, potentially owing to greater ionic and hydrophobic interactions.

Extended Data Figure 4 Site-directed mutagenesis of selected residues at the LeuT dimer interface, resulting mass spectra and molecular dynamics simulations.

a, Mass spectrum of LeuT F488A/Y489A, liberated from octylglucoside micelles, reveals monomeric LeuT (green spheres). Inset shows the LeuT dimer interface, with key π-stacking interactions (yellow dotted lines, distances labelled in red) and between aromatic residues (purple). When residues F488 and Y489 (orange arrows) are mutated to alanine, the π-stacking interactions are abolished and LeuT cannot dimerize. b, Molecular dynamics simulations of LeuT in an E. coli lipid bilayer reveal possible binding sites of interfacial phospholipids and cardiolipin (upper panel, viewed from cytoplasmic side of membrane). The cardiolipin phosphate groups (orange) interact closely with positively charged residues (K376, H377, R506; blue) at the dimer interface. Phosphoethanolamine (PE) and phosphatidylglycerol (PG) also bind at the dimer interface. c, Mass spectrum of LeuT expressed in a cardiolipin-deficient E. coli strain (BKT22), liberated from octylglucoside micelles, shows monomeric LeuT, implying that cardiolipin is required for LeuT dimerization. d, Mass spectrum of LeuT K376A/H377A, liberated from octylglucoside micelles, shows monomeric LeuT.

Extended Data Figure 5 CGMD simulations on LeuT and NhaA dimer.

a, Particle densities from five repeats of 1-μs CGMD simulations for cardiolipin around LeuT. The surface densities represent the most occupied positions from the simulations of the phosphate (orange), glycerol (red) and alkyl tails (purple) particles of cardiolipin. The proposed binding sites at the interface are the only places where cardiolipin shows considerable population density. bd, Comparative particle densities of cardiolipin (b), phosphatidylglycerol (c) and phosphoethanolamine (d) at the LeuT dimeric interface, summed over the simulations show no or minimal densities for phosphatidylglycerol and phosphoethanolamine at the cardiolipin-binding site. Together, ad show that the proposed binding sites of cardiolipin at the interface are sites of specific bindings. e, Dimeric structure of LeuT with modelled APT (aminopentanetetrol, aminophospholipids) classes of lipid present in A. aeolicus52. The lipid was drawn in ChemDraw and subsequently modelled by superimposition onto cardiolipin to give the cardiolipin-bound dimeric structure. The favourable van der Waals distances show that it is capable of bridging the dimeric entity through the same sets of residues that were found to be critical towards cardiolipin binding, in an endogenous environment lacking cardiolipins. f, Particle densities from five repeats of 1-μs CGMD simulations for cardiolipin (phosphate group in orange, glycerol in red and alkyl tails in purple) and POPG (in blue) around NhaA dimer interface. As before, the density of cardiolipin is considerably higher than that of phosphatidylglycerol. However, unlike LeuT, here the difference between the density of cardiolipin and phosphatidylglycerol is lower, suggesting this site has less exclusivity towards cardiolipin than that in LeuT. Indeed, mass spectrometry analysis shows a heterogenous distribution of lipids with dimeric NhaA, with mostly cardiolipin but some amount of bound phospholipids.

Extended Data Figure 6 Mass spectra of His-tagged and unmodified SemiSWEET and identification of endogenous and exogenous lipid binding.

a, Mass spectrum of unmodified SemiSWEET, liberated from tetraethyleneglycolmonooctyl ether (C8E4) micelles, reveals SemiSWEET monomers and dimers (black spheres). b, Mass spectrum of deca-His tagged SemiSWEET, liberated from C8E4 micelles, reveals SemiSWEET monomers and dimers (green spheres). c, High energy MS/MS of unmodified SemiSWEET, liberated from dodecylmaltoside (DDM) micelles, allows isolation of the 6+ charge state (black spheres) of the SemiSWEET monomer (black spheres) bound to endogenous lipids. Fragmentation of the lipid-bound species leads to loss of either cardiolipin (1,470 ± 26 Da, purple head-groups), one or two neutral phospholipids (each 756 ± 22 Da, blue head-groups), or a positively charged phospholipid. Trap collision voltages are shown in white inside the blue arrow. d, Mass spectrum of deca-His SemiSWEET, liberated from C8E4 micelles and incubated with phosphatidylglycerol (blue head-groups). phosphatidylglycerol binds to both monomers and dimers (dotted boxes highlight lipid-bound peaks) without substantial preference. e, Mass spectrum recorded after incubation in solution of an equimolar ratio of deca-His tagged and untagged SemiSWEET (green and black spheres, respectively), liberated from tetraethyleneglycolmonooctyl ether (C8E4) micelles. Plot of the percentage abundance of hetero- and homodimers over time (inset), SemiSWEET heterodimers (red trace, peaks highlighted red in mass spectrum) and homodimers (black trace), revealing the solution-phase monomer–dimer equilibrium (PDB accession number: 4QND).

Extended Data Figure 7 Mass spectrum and high-energy MS/MS of NhaA at a range of collision voltages.

a, Mass spectrum of NhaA, liberated from C8E4 micelles, reveals NhaA monomers (green spheres) bound to cardiolipin (purple head-groups) and an ensemble of NhaA dimer species in different lipidation states (highlighted in green). b, MS/MS of the 15+ charge state (green) of the NhaA dimer (green/black spheres) bound to two cardiolipin molecules liberated from C8E4 micelles. Increasing collision voltage applied to the 2× cardiolipin-bound species leads either to loss of 1 cardiolipin to form NhaA dimers bound to 1 cardiolipin (40 V) or to loss of 2 cardiolipin molecules to form delipidated NhaA dimers, with concomitant generation of NhaA monomers (70 V) and further dissociation of NhaA dimers into monomers (120 V). Trap collision voltages are depicted in white, inside the blue arrow.

Extended Data Figure 8 Sequence and structure alignment of LeuT with other eukaryotic biogenic transporters.

a, The basic residues of LeuT that are involved in lipid binding (red box) are conserved across the BATs. b, Two views of the superimposed structures of LeuT (PDB accession number: 2A65, black) and SERT (PDB accession number: 5I6Z, light blue) show the differences in the dimer interface. Dimer interface helices are highlighted with arrows and coloured (LeuT, green; SERT, red); basic residues responsible for lipid binding in LeuT are shown in yellow mesh. One of the interface helices in SERT swings away from the interface, negating the possibility of lipid-induced oligomerization, analogous to that proposed for LeuT.

Extended Data Table 1 Summary of the mass spectral analysis of membrane proteins forming strong oligomers

Supplementary information

Supplementary Table 1

Total buried surface area and the number salt bridges for each of the oligomeric proteins. The respective PDB IDs are also provided (XLSX 22 kb)

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Gupta, K., Donlan, J., Hopper, J. et al. The role of interfacial lipids in stabilizing membrane protein oligomers. Nature 541, 421–424 (2017).

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