The plasma membrane is a network of lipids and proteins that serves as a physical barrier between the external environment and the interior of the cell. The maintenance of plasma membrane tension homeostasis is vitally important to prevent cancer metastasis, neurodegeneration, and metabolic syndrome. However, the study of this important process has lagged due to a lack of tools to measure and manipulate the behavior of lipids in the context of cellular membranes.
Starting from the observation that a small molecule, palmitoylcarnitine (PalmC), discovered in a screen in our lab, is able to induce membrane tension loss and plasma membrane invaginations, and inhibit the activity of the signaling complex that serves as a master regulator of membrane tension (TORC2), our aim was to characterize the mechanism by which PalmC alters plasma membrane tension (Aim 1). Our studies have revealed that PalmC, in addition to other small amphipathic molecules, acts directly on the plasma membrane and achieves its effects in a sterol-dependent manner.
During the course of this work, we also made a serendipitous discovery while purifying native TORC2 protein from yeast cells (Aim 2). We isolated a membrane-bound structure of the eisosome, a unique plasma membrane microdomain found in yeast which senses membrane stress and initiates signaling to TORC2. These isolated native eisosomes, scaffolded by the BAR-domain proteins Pil1 and Lsp1, were bound to a plasma membrane bilayer (See figure). By solving cryoEM structures of these native eisosomes, we were able to observe that the bound membrane has a remarkably well-organized structure with signatures of specific lipid species discernable within the membrane bilayer. These native eisosomes and their high-resolution structures have provided us a unique window into the organization of the lipids within a membrane microdomain.
