Abstract
Membrane lipids act as solvents and functional cofactors for integral membrane proteins. The yeast plasma membrane is unusual in that it may have a high lipid order, which coincides with low passive permeability for small molecules and a slow lateral diffusion of proteins. Yet, membrane proteins whose functions require altered conformation must have flexibility within membranes. We have determined the molecular composition of yeast plasma membrane lipids located within a defined diameter of model proteins, including the APC-superfamily lysine transporter Lyp1. We now use the composition of lipids that naturally surround Lyp1 to guide testing of lipids that support the normal functioning of the transporter, when reconstituted in vesicles of defined lipid composition. We find that phosphatidylserine and ergosterol are essential for Lyp1 function, and the transport activity displays a sigmoidal relationship with the concentration of these lipids. Non-bilayer lipids stimulate transport activity, but different types are interchangeable. Remarkably, Lyp1 requires a relatively high fraction of lipids with one or more unsaturated acyl chains. The transport data and predictions of the periprotein lipidome of Lyp1 support a new model in which a narrow band of lipids immediately surrounding the transmembrane stalk of a model protein allows conformational changes in the protein.
Highlights
In the fluid mosaic bilayer model [1], lipids are seen as solvent for integral membrane proteins like aqueous media are for soluble proteins
Sterols can increase the order of the acyl chains [7], which is accompanied by a decrease of the lateral diffusion of components in the membrane [8]
The yeast sphingolipids and certain phospholipids with precisely matching head-group-acyl chain combinations identified in our periprotein lipidome analyses are not available, but we could design lipid mixtures that otherwise mimic periprotein lipids in yeast cells
Summary
In the fluid mosaic bilayer model [1], lipids are seen as solvent for integral membrane proteins like aqueous media are for soluble proteins. The length of the lipids should approximately match the hydrophobic region of the protein, and the polar head-groups of the lipids can interact with the hydrophilic regions of the membrane protein [2]. These parameters are referred to as hydrophobic–hydrophilic matching of proteins and lipids [3], which has been shown to affect the activity and or stability of membrane proteins [4,5,6]. Sphingolipids typically have saturated long-chain fatty acids and preferentially interact with sterols, giving rise to so-called liquid-ordered membrane domains that are phaseseparated from more fluid domains [9]. The hydrophilic heads of phosphatidylglycerol (PG) and -serine (PS) lipids form hydrogen bonds with polar amino acids, and salt-bridges can be formed between basic residues on the protein and the lipid phosphate [10]
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