College of Liberal Arts & Sciences

Lipid bilayers as regulators of membrane protein function

September 22, Tue 2009
1:00 pm, MRB 200 Conference Room

Dr. Olaf S. Andersen

Department of Physiology and Biophysics, Weill Medical College of Cornell University

Membrane protein function is regulated by the host lipid bilayer. This regulation can be: specific (lipid-dependent), due to specific lipid-protein interactions; non-specific (bilayer-dependent), due to changes in bilayer material properties (bilayer thickness, lipid intrinsic curvature and bilayer elastic moduli); or combination of the two. The bilayer-dependent regulation arises from hydrophobic coupling between a bilayer-spanning protein and the lipid bilayer, which causes protein conformational changes that involve the bilayer-spanning domain to alter the local lipid packing in the vicinity of the protein. The associated bilayer deformation energy contributes to the free energy difference of the protein conformational change. Because the bilayer deformation energy varies with changes in the chemical composition of the bilayer—including the adsorption of small amphiphiles at the bilayer/solution interface—the bilayer becomes a regulator of membrane protein function. The seminar will describe experimental approaches to measure drug-induced changes in bilayers properties relevant for the regulation of membrane protein function.

One can measure the energetic consequences of changes in bilayer material properties because the bilayer responds to a protein-induced deformation by imposing a restoring force, which can be measured using a suitable reporter. The bilayer-spanning gramicidin channels turn out to be useful reporters because they form by trans-bilayer dimerization, such that the bilayer responds to the deformation associated with channel formation by imposing a disjoining force (Fdis) on the channels. Changes in the bilayer deformation energy, and thus Fdis, result in changes in the rate constants for channel formation and dissociation, which are measurable as changes in channel appearance rate (&fnof) and lifetime (&tau). Operationally, changes in bilayer properties that at a constant thickness alter Fdis are defined as changes in bilayer stiffness. Maneuvers that decrease bilayer stiffness decreases Fdis, which increases &fnof and &tau, and vice versa for maneuvers that increase bilayer stiffness. One thus can quantify the amphiphile-induced changes in bilayer material properties in terms of changes in bilayer stiffness.

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