Transverse and Lateral Structure

(supported by the Austrian Science Fund, Project No. P27083-B20)

start of project: October 1, 2014
end of project: September 30, 2017

All biological cells are bordered a plasma membrane, which enables diverse physiological functions, including cellular communication and selective material transport into or out of the cell. The molecular composition of these outer membranes is complex involving as a central element a lipid/protein bilayer. Lipids are known to form the structural matrix of this layer embedding proteins with specific functions (e.g. pumps, ion channels, receptors), but are increasingly recognized for their functional role. For example, lipid disorder has been implicated in diverse diseases including cancer, diabetes type II, or Parkinson to name but a few.

One of their physiological roles is to assist the formation of lipid/protein platforms, known as "membrane rafts", which fulfill specific functions. Consequently membrane lipids are not equally distributed laterally, but segregated into certain domains. Moreover, plasma membranes typically display also transbilayer asymmetry, i.e. lipids are not homogeneously distributed within the two membrane leaflets. Mammalian plasma membranes, for example, actively sequester nearly all of its sphingomyelin and phosphatidylcholine lipids within the outer leaflet, while phosphatidylethanolamine and the negatively charged lipids phosphatidylserine and phosphatidylinositol are found in the inner leaflet.

Biophysical studies on artificial membranes mimicking plasma membrane have yielded significant insight on the active role of membrane lipids. For example, model membranes composed of lipids exclusively found in the outer membrane leaflet show the formation of domains. Interestingly, when repeating the same experiments with lipids of the inner leaflet no domains are observed. However, when constructing asymmetric lipid membranes with domain-forming lipids in the outer and non-domain-forming lipids in the inner leaflet, segregation of inner membrane lipids was observed. Hence, there must be a coupling mechanism which may originate from hydrocarbon chain interdigitation, cholesterol flip-flop, or curvature-tension related mechanisms. Understanding this transmembrane coupling is a key to our understanding of membrane function. Experimental studies on artificial asymmetric bilayers are sparse and consequently no clear-cut picture of transversal and later coupling in asymmetric membranes is available at present. Most recent developments in sample preparation allow high-resolution structural studies via combination of x-ray and neutron scattering experiments with molecular dynamics simulations. Thereby we will specifically study the nature of transmembrane coupling, determine the structural properties of domains in asymmetric bilayers and measure the preferred location of cholesterol in both membrane leaflets.

We have assembled an international consortium of key researchers that will team-up to meet the goals of the project. It is expected that the proposed work will enable several future studies related to the influence of membrane asymmetry on protein function and the role of membrane active compounds, such as medical drugs.