Lipid rafts are nano- to micron-sized regions within the plasma membrane characterized by a high local concentration of cholesterol and lipids with saturated fatty acid chains. The raft phases segregate proteins by partitioning raft-associating proteins to be in close proximity to one another. Over the years, lipid rafts have become associated with disease states such as Alzheimer’s, Parkinson’s, cardiovascular and prion diseases, several forms of cancer, systemic lupus erythematosus and HIV. While progress has been made in characterizing the raft phase, there is still need for considerable advancement in understanding how rafts form and function. The goal of this work is to advance the use of the lipid raft concept in medicine by using molecular modeling and theoretical approaches to determine the impact of lipid-lipid and protein-lipid interactions on the structure and functionality of the cell membrane.Understanding the synergistic molecular reorganization of GPI-anchored and RAS proteins inserted into model lipid layers has the potential to identify new drug targets by elucidating the nature of the lateral inhomogeneities in the plasma membranes and their role in cell function. We are currently determining the partitioning of H-RAS, K-RAS, and common GPI-anchored proteins into raft and non-raft phases as a function of membrane curvature.We are also working to quantify the effect of cylindrical versus spherical vesicles on the difference in partitioning of GPI-anchored and RAS proteins into raft and non-raft phases as a function of curvature.Curved cellular membranes typically display precisely defined and distinct types of curvature, e.g. spherical (trafficking- and synaptic vesicles) and cylindrical (tubes in the ER and Golgi). This work will determine if differences in the type of membrane curvature regulate the recruitment of membrane-binding proteins to cellular membrane compartments.
• Membrane Curvature Enables N-RAS Lipid Anchor Sorting to Liquid-Ordered Membrane Phases. J. Larson, M. B. Jenson, V. K. Bhatia, S. L. Pederson, T. Bjornholm, L. Iverson, M. J. Uline, I. Szleifer, K. J. Jensen, N. S. Hatzakis, and D. Stamou, Nature Chemical Biology, 11, pages 192-194 (2015) (Brief Communication – Cover Article)
• Mode Specific Elastic Constants for the Gel, Liquid-Ordered, and Liquid-Disordered Phases of DPPC/DOPC/Cholesterol Model Lipid Bilayers. M. J. Uline and I. Szleifer, Faraday Discussions, 131, pages 177-191 (2013)
• Calculating Partition Coefficients of Chain Anchors in Liquid-Ordered and Liquid -Disordered Phases. M. J. Uline, G. S. Longo, M. Schick, and I. Szleifer, Biophysical Journal, 98, pages 1883-1892 (2010)