Membrane architecture and the interplay of complex lipid structures and integral protein functions
The architecture of plasma membranes and membranes of subcellular compartments is composed of integral membrane proteins with divergent functions embedded in an array of amphipathic complex phospho-(PL) and sphingolipids (SL). The polar head groups of PL and SL are asymmetrically arranged at the surface of the inner and outer leaflet of the bilayer. The glycerophosphate backbone of phospholipids is asymmetrically substituted by saturated, mono- and polyunsaturated fatty acids and the sphingosine backbone preferentially with saturated and monoenoic long chain fatty acids, forming the hydrophobic scaffold of integral proteins and essential for understanding specific functions of membrane functions. My overall research addresses the enigmatic molecular mechanisms underlying the structural complementarity of different PL and SL classes and specific for functional integrity.
Our experimental strategy comprises deletion of gene expression of a respective integral membrane protein with structural, adhesive, transporter, enzyme function by homologous recombination in the mouse. Phenotyping of these in vivo mutants using the armory of biochemical, molecular and cell biological techniques provide undoubtful insight into the physiological and pathophysiological role of the protein or lipid class under study.
These studies have provided fundamental insight into the architecture of the oligodendrocyte derived myelin membrane and its functional implications, into the complete pathways of ana- and catabolism of sphingosine bases. They led to the discovery of the first glutamate neurotransmitter transporter GLAST1 (EAAT1).
We targeted the key enzymes of sphingomyelin catabolism and ceramide functions and finally of the metabolism of mono- and polyunsaturated fatty and generated the null-allelic mouse models for the metabolism and their structural and functional implications in the bilayer in the stearoyl-CoA desaturase (scd1) and most recently of the ω6-desaturase (fads2) null allelic mouse, a mutant which proved to be auxotrophic. Dietary studies allow therefore the definition of the physiological and pathophysiological role of essential fatty acids 18:2 and α-18:3 and individual ω3- and ω6 polyunsaturated fatty acids (PUFAs).
Our experimental strategies including the high resolution techniques of lipidomics reveal unprecedented insight into the decade old debate on ω3/ω6- PUFAs in nutrition, their functions in lipid structures and their role as epigenetic factors in a broad pathophysiology. These studies may finally lead into well designed bench to bedside therapeutic approaches by nutritional intervention.