Liquid-ordered lipid domains, also called rafts, are assumed to be important players in different cellular processes, mainly signal transduction and membrane trafficking. They are thicker than the disordered part of the membrane and are thought to form to compensate for the hydrophobic mismatch between transmembrane proteins and the lipid environment. Despite the existence of such structures in vivo still being an open question, they are observed in model systems of multicomponent lipid bilayers. Moreover, the predictions obtained from model experiments allow the explanation of different physiological processes possibly involving rafts. Here we present the results of the study of the regulation of raft size distribution by ganglioside GM1. Combining atomic force microscopy with theoretical considerations based on the theory of membrane elasticity, we predict that this glycolipid should change the line tension of raft boundaries in two different ways, mainly depending on the cholesterol content. These results explain the shedding of gangliosides from the surface of tumor cells and the following ganglioside-induced apoptosis of T-lymphocytes in a raft-dependent manner. Moreover, the generality of the model allows the prediction of the line activity of different membrane components based on their molecular geometry.

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Anaerobic ammonium oxidizing (anammox) bacteria form a critical part of the nitrogen cycle by converting ammonium and nitrite to nitrogen gas. Anammox bacteria carry out their metabolism in the anammoxosome, a membrane-bound organelle that is comprised of the unique ladderane lipids. Ladderane lipids, named for the ladder-like structure of fused cyclobutane rings in their fatty acid tails, have not been found anywhere else in nature, suggesting that they play a critical role in the anammox metabolism. It has been hypothesized that ladderane lipids prevent the diffusion of hydrazine (an anammox intermediate), protons, or other species across the anammoxosome membrane. As anammox bacteria have not been grown in axenic culture and grow extremely slowly in enrichment cultures, researchers have not been able to isolate sufficient quantities of pure ladderane lipids to determine the biophysical properties of ladderane membranes. Without knowledge of the physical properties of ladderane lipids or genetic tools for studying the lipids in vivo, their biological function remains unknown. We have developed efficient synthetic routes to naturally occurring ladderane phospholipids and unnatural analogs. We show that ladderane lipids have physical properties that are distinct from conventional straight-chain lipids. Ladderane lipids form dense bilayers with slow lateral diffusion and dense monolayers with low compressibility. By varying the identities of the fatty acid tails, we establish structure-function relationships for the different ladderane structures. These physical properties result in membranes with much slower rates of transbilayer diffusion of protons, which are pumped across the anammoxosome membrane and used to produce ATP. These results suggest that ladderane lipids in the anammoxosome may prevent the dissipation of the proton gradient during the slow anammox metabolism. This role for ladderane lipids in the anammoxosome may partially explain why anammox bacteria evolved such unique lipids.