Molekulare Mechanismen des Zwiegesprächs von Proteinumsatz und Membranfluidität

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Membrane fluidity is essential for life and tightly controlled within a narrow regime. The fluidity of a complex biological membrane is largely dependent on the fraction of saturated and unsaturated fatty acids incorporated into membrane lipids. Even though the mechanisms of fatty acid desaturation have been intensively studied, the molecular sensors of membrane fluidity are not known. Using and quantitative, mass-spectrometry based lipidomics of Saccharomyces cerevisiae, we will screen for genes that affect lipid saturation in vivo and study the mechanism behind their effects in vitro by purification and reconstitution in defined membrane environments. I have recently identified a component of the endoplasmic reticulum (ER) quality control machinery as a putative sensor of membrane fluidity and could demonstrate its capacity to bind unsaturated fatty acids. These findings lead to my hypothesis that the substrate spectrum of the machineries responsible for turnover of ER-derived proteins is directly modulated by fatty acids, and that these mechanisms are responsible for membrane fluidity homeostasis. To test this hypothesis, I have developed methods to fine-tune the cellular lipidome with respect to lipid saturation and will quantify the effects of these pertubations protein turnover and secretion. This proposal aims at a better understanding of the molecular mechanism underlying membrane lipid and protein homeostasis and the underlying molecular mechanisms.