Contribution to the special BBA issue dedicated to Joachim Seelig - From lipid bilayers to the innate immune system.

This personal review in memory of Joachim Seelig covers half a century of membrane biophysics. The topics chosen give insight into the structure and function of our innate immune system, consisting in the membranes covering the external and internal body surfaces in contact with the outside world. Their core is the lipid bilayer in its liquid crystalline state. We investigated its average structure and fluidity by deuterium-nuclear magnetic resonance spectroscopy (D-NMR) using selectively deuterated lipids. Close to the lipid-water interface, lipids retain a defined average structure with the glycerol backbone oriented perpendicular to the membrane surface. The characteristic structure of lipids remains in the presence of transmembrane proteins and guarantees a tight membrane packing near the aqueous phases. The order of lipid segments remains approximately constant decreasing only towards the membrane center. Were cells surrounded by lipids only, hydrophobic molecules would nevertheless penetrate the membranes and reach the nucleus, the smaller ones more rapidly and the larger one more slowly. To protect cells from intruding mutagenic compounds, a significant number of defense proteins have evolved, including ATP binding cassette (ABC) transporters and pattern recognition receptors (PRR). Interestingly, the different defense proteins recognize compounds that carry specific hydrogen bond acceptor patterns and could interfere with DNA or RNA. ABC transporters and pattern recognition receptors remove them from the lipid bilayer before they reach the cytosol to prevent mutagenesis. While these proteins are well known to contribute to multidrug resistance (MDR), their significant role in innate immunity only starts to emerge.