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The role of interfacial lipids in stabilizing membrane protein oligomers
Membrane lipids such as cardiolipin act as molecular glue to preserve the oligomeric states of membrane proteins with low oligomeric stability. Membrane-protein stabilization by lipid binding It is well established that lipid binding leads to the oligomerization of membrane proteins, and hence the a...
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Published in: | Nature (London) 2017-01, Vol.541 (7637), p.421-424 |
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Main Authors: | , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
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Summary: | Membrane lipids such as cardiolipin act as molecular glue to preserve the oligomeric states of membrane proteins with low oligomeric stability.
Membrane-protein stabilization by lipid binding
It is well established that lipid binding leads to the oligomerization of membrane proteins, and hence the activation of many signalling pathways, but it is not clear how the lipid bilayer affects the structure and function of membrane–protein complexes. Carol Robinson and colleagues have developed a mass-spectroscopy-based technique that allows the observation of oligomeric membrane–protein complexes with sufficient resolution to characterize their bound lipids. Using this technique, they evaluate the strength of oligomer formation for some 125 α-helical membrane proteins, including G-protein-coupled receptors. They find that lipid binding modulates protein interfaces, perturbing their monomer–oligomer equilibria, and show that manipulation of lipid binding can modify oligomer stability. And they use modelling to investigate possible binding sites for lipid molecules at the interfaces involved in oligomerization. These findings could aid the optimization of membrane–protein complexes for structural analysis.
Oligomerization of membrane proteins in response to lipid binding has a critical role in many cell-signalling pathways
1
but is often difficult to define
2
or predict
3
. 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 (LeuT
4
, 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 SemiSWEET
5
, another protein with low oligomeric stability, cardiolipin shifts the equilibrium from monomer to functional dimer. We hypothesized that lipids |
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ISSN: | 0028-0836 1476-4687 1476-4687 |
DOI: | 10.1038/nature20820 |