Protein–fatty acid complexes: biochemistry, biophysics and function

Abstract

Thirteen years ago, α‐lactalbumin (α‐LA) was first reported to form a complex with oleic acid (OA). This complex, called HAMLET (human α‐lactalbumin made lethal to tumour cells), was found to be cytotoxic to cancer cells. In HAMLET, α‐LA assumes a partially unfolded conformation and can bind OA in various stoichiometries. Subsequently, different groups have been able to prepare HAMLET‐like cytotoxic complexes in different ways, which all involve the destabilization of α‐LA, and a number of different proteins have been able to form similar complexes. This suggests that the ability to form stable complexes with lipids may be a generic feature of the polypeptide chain, although the precise structural and functional details may vary from protein to protein. We review the biophysical and biochemical properties of this class of complexes, focusing on different methods of preparation, complex structure and the role of the protein and the lipid within these complexes. The cellular effects of these complexes are multifaceted and depend on the cell types. There are strong indications that OA has an essential role, whereas the protein component, rather than having a toxic effect on its own, functions as a vehicle for transporting the toxic OA to the cells and keeping the OA in solution. Fatty acids alone can affect numerous cellular signalling and metabolic pathways, in addition to playing important roles in immune responses and inflammatory processes. Further studies will aim to determine how the molecular properties of the different protein–lipid complexes correlate with their biological efficacy.

Direct observation of alpha-lactalbumin, adsorption and incorporation into lipid membrane and formation of lipid/protein hybrid structures

“…1-3 together, it is possible to say that α-La insertion into membrane leads to changes in liposome morphology, being this dependent on the L/P ratio and in line with the literature [13,15,28,45,52,73,74,84,85]. Importantly, structural perturbations of the membrane and lipid reorganization are also dependent on the concentration of the protein partitioned into or adsorbed to the membrane surface [85,86]. Indeed, for globular proteins and below a certain concentration, adsorption to lipid bilayer is suggested to happen along with small membrane reorganization [85].…”

A Protein Complex from Human Milk Enhances the Activity of Antibiotics and Drugs against Mycobacterium tuberculosis

“…This is consistent with our finding that HAMLET was more active against M. tuberculosis with increasing oleic acid content. The function of the protein component, e.g., ␣-lactalbumin in HAMLET, is believed to increase the solubility of the fatty acid by shielding it from water (61,62,66). Our observation that HAMLET is approximately 10-fold more efficient in killing M. tuberculosis than the same molar amount of oleic acid, while ␣-lactalbumin had no significant effect on the viability of M. tuberculosis in vitro (Fig.…”

A long-chain fatty acid elongase Elovl6 regulates mechanical damage–induced keratinocyte death and skin inflammation

“…Elovl6 -/mice than in wild-type mice, presumably owing to its efficient conversion to 217 transmembrane potential, activation of caspase-3, and the production of reactive oxygen 241 species (Brinkmann et al 2013;Fontana et al 2013). In the current study, we found that, 242 beginning soon after its addition to the cultures, CVA was severely cytotoxic to HaCaT 243 cells, mouse peritoneal macrophages, and primary keratinocytes; CVA can thus be 244 added to the list of possible lipotoxins.…”