June 2010

Exploring Membranes: The Work of Sarah L. Keller

Figure 1. A collection of fluorescence images of vesicles (lipid membranes in the shape of a spherical shell of roughly 20-100 micrometers in diameter). Each membrane contains a mix of lipid types, including one that is labeled with a fluorescent probe and appears bright. The lipids in some membranes are uniformly mixed, and the vesicle appears uniformly bright across its surface. The lipids in other membranes have segregated into domains, which are enriched in particular lipids, so the membrane exhibits contrasting bright and dark regions. Composite image by Aurelia Honerkamp-Smith.

Cell membranes are composed of a broad spectrum of lipids and proteins. The behavior of membranes, even “simple” model membranes that contain only lipids and no proteins, is remarkably rich. For example, lipids in a membrane respond to particular changes in temperature or overall membrane composition by undergoing a miscibility transition. This means that lipids in a uniform membrane suddenly sort into distinct regions that are enriched in different lipid types. Sarah L. Keller, a professor of chemistry at the University of Washington and the inaugural Avanti Young Investigator in Lipid Research Awardee, uses fluorescence microscopy to visualize these membrane regions and to identify the temperatures and compositions at which miscibility transitions occur. One of the lipid types is labeled with a molecule that fluoresces. Regions of the membrane that are enriched in this fluorescently labeled lipid appear bright in their images (Figure 1).

Miscibility transitions affect not only a membrane’s lipids but also its proteins. A protein that is located in the middle of a membrane domain may behave very differently from an identical protein that is located in the surrounding membrane or in a uniform membrane. As a specific example from Keller’s work, alamethicin molecules form ion channels in membranes. The channel adopts a structure that conducts more ions when the channel resides in membranes made of one lipid type (phosphatidylcholines) than another type (phosphatidylethanolamines).

Recently, Keller and her group turned their attention to asymmetric membranes, inspired by the observation that the inner and outer leaflets of cell membranes have strikingly different lipid compositions. The two leaflets also are assumed to differ in their ability to form membrane domains. The Keller group showed that liquid domains in the outer leaflet can induce domains in the inner leaflet of an asymmetric, protein-free Montal-Mueller bilayer. Furthermore, by tuning the lipid composition of only one of the leaflets, they were able to suppress domains in the entire bilayer. Induction of domains across asymmetric membranes has strong relevance to questions in cell biology as it may prove to be a mechanism for colocalization of inner and outer leaflet proteins during cell signaling events.

Keller has been recognized not only for her interdisciplinary research, but also for her mentoring and teaching. She was given the University of Washington Distinguished Teaching Award in 2006 and the department of chemistry Outstanding Teaching Award in 2004. The students and postdoctoral fellows who work with her have been recognized with their own honors. Her first doctoral student, Sarah Veatch, was awarded a National Institutes of Health Pathway to Independence Award and will join the biophysics faculty at the University of Michigan this summer. Her most recent doctoral student, Aurelia Honerkamp-Smith, was just awarded the Anna Louise Hoffman Award for Outstanding Achievement in Graduate Research by Iota Sigma Pi, the national honor society for women in chemistry.

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