Membrane recognition by an ER lipid sensor complex

Cellular membranes are 10.000 times thinner than a human hair yet composed of thousands of distinct lipids and proteins. A significant portion of the human genome encodes for machineries producing, modifying and degrading membrane lipids. Because of their stunning diversity it is extremely challenging to study lipid function and the purpose of lipid diversity remains elusive. What is known, however, is that numerous devastating diseases such as Parksinsons, Alzheimerssand cancercorrelate with perturbed membranelipid compositions. A disorder in lipid metabolism is also a major cause of the metabolic syndrome, leading to disease states including type 2 diabetes and cardiovascular diseases. The molecular role of lipids in the pathogenesis of these diseases, however, remains poorly understood. This proposal aims to reveal the molecular mechanism underlying the cellular decision between membrane growth and fat storage. When does a cell decide to resume growth and to store fat instead? And how does a cell orchestrate the challenging task to reprogram its lipid metabolism from growth to storage? These important questions will be addressed in the model organism bakers yeast (Saccharomyces cerevisiae), whose metabolism is remarkably similar to human cancer cells. The research focuses on phosphatidic acid, a class of lipid molecules with a tremendous potential to control these cellular decisions: only when phosphatidic acid is abundant, the cell will invest its energy to grow new membranes. The cellular response to this class of signaling lipids it mediated by a sensor protein, called Opi1, communicating the phosphatidic acid content to the nucleus. The dynamic behavior of this sensor molecule will be studied using fluorescence microscopic inspections and Opi1 mutant variants with designed properties to tune the cellular response to metabolic stress. Using Opi1, the key regulator of lipid metabolism in yeast, as a show box, this proposal aims at a better understanding of the fundamental mechanisms underlying membrane recognition. The characterization of Opi1s peculiar properties will provide a new perspective for the rational design of specific lipid sensors with high selectivity to distinct organellar membranes.

Molecular interactions between biomolecules must function smoothly in a way that highly complex processes in the cell can be conducted in an orderly fashion. Disturbed interactions can trigger a variety of diseases, so it is essential to study these interactions in great detail. Within the framework of my Erwin-Schrödinger project, the extremely important role of biological membranes in protein-membrane interactions was considered. Such membranes delimit a cell to the outside or form partitioned areas within a cell and are composed of various special fats (lipids). They determine the membranes stability, dynamics and high flexibility. The crucial membrane properties for its distinct function are controlled by special membrane sensors, which may also initiate appropriate cellular repair processes if the lipid composition is disturbed. So far, the selectivity of this membrane recognition process is yet poorly understood. During my stay abroad in the group of Dr. Robert Ernst in Frankfurt/Main we now found that certain structures in these lipid sensors, so-called amphipathic helices, are responsible for recognizing not only the individual lipid composition but also specific biophysical properties such as membrane fluidity and membrane curvature. There seems to be some sort of hidden membrane recognition code in these amphipathic helices to detect membrane properties and to initiate cellular responses to intolerable abnormalities or even to declare a cellular state of emergency. These molecular findings provide an important contribution to the understanding of specific protein-membrane interactions and may be very useful for the development of novel antibiotics based on membrane-active antimicrobial peptides.