Liprotides made of α-lactalbumin and cis fatty acids form core–shell and multi-layer structures with a common membrane-targeting mechanism

• Liprotides are protein–fatty acid complexes with partially denatured proteins.
• Only cis fatty acids can form liprotides.
• Liprotides prepared by heat treatment have intermolecular disulfide bonds.
• Small liprotides form a core–shell and larger liprotides a multi-layer structure.
• Liprotides can transfer fatty acids to membranes and are cytotoxic.

α-Lactalbumin (aLA) has been shown to form complexes with oleic acid (OA), which may target cancer cells. We recently showed that aLA and several other proteins all form protein–OA complexes called liprotides with a generic structure consisting of a micellar OA core surrounded by a shell of partially denatured protein. Here we report that a heat treatment and an alkaline treatment method both allow us to prepare liprotide complexes composed of aLA and a range of unsaturated fatty acids (FA), provided the FAs contain cis (but not trans) double bonds. All liprotides containing cis-FA form both small and large species, which all consist of partially denatured aLA, though the overall shape of the species differs. Small liprotides have a simple core–shell structure while the larger liprotides are multi-layered, i.e. they have an additional layer of both FA and aLA surrounding the outside of the core–shell structure. All liprotides can transfer their entire FA content to vesicles, releasing aLA as monomers and softening the lipid membrane. The more similar to OA, the more efficiently the different FAs induce hemolysis. We conclude that aLA can take up and transfer a wide variety of FA to membranes, provided they contain a cis-bond. This highlights liprotides as a general class of complexes where both protein and cis-FA component can be varied without departing from a generic (though sometimes multi-layered) core–shell structure.

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