Membrane Mechanics and Mechanosensitive Ion Channels
The main theme of mechanosensitive ion channel research in the Phillips Group is aimed at understanding two general classes of problems.
1) Mechanosensitivity by itself is a general term to describe how cells respond to changes in their mechanical environment - from physical touch on the plasma membrane by external objects or the polymerization of actin, to osmotic stresses in the environment. Our group has focused on a well characterized mechanosensitive protein known as the Mechanosensitive Channel of Large Conductance (MscL), found in the plasma membrane of E. coli (and other bacteria). This protein is responsible for managing the mechanical stresses present during osmotic down-shock. MscL senses the tension in the membrane and changes to an open conformation to release osmolytes and water, thereby equilibrating the otherwise lethal osmotic pressure gradient.
But how does MscL sense tension in the membrane? How do the elastic properties of the surrounding lipids affect the function of the channel? For that matter, how do the elastic properties of the lipids affect the function of any channel or transmembrane protein? In a continuum elastic model, the bilayer can affect proteins through its bending stiffness, resistance to area dilation, resistance to compression, and its hydrophobic thickness. We find that hydrophobic mismatch, most strongly related to compression deformations, has a severe effect on the function of MscL. Indeed, other experimental work has shown this qualitatively. We are moving towards a detailed electrophysiological study of the interplay between membrane tension and the mismatch between the hydrophobic regions of the protein and the bilayer.
Figure 1. Hydrophobic mismatch and a protein's shape deform the surrounding bilayer in a quantifiable way. Here, a protein induces hydrophobic mismatch, midplane bending and leaflet bending - all of which can be translated into forces which the protein must resist. However, these forces can have profound effects on the energetics of conformation.
2) Our understanding of the bilayer deformations which surround transmembrane proteins led us to wonder if there could be communication between neighboring proteins that is mediated strictly by the elastic nature of the bilayer. We found that the finite decay length of the elastic deformations around a transmembrane protein lead to interactions between neighboring proteins. In fact, these so-called elastic interactions tend to couple the conformational states of proteins in proximity, and lead to conformationally dependent spatial organization within the membrane. With some knowledge of the open and closed structures of MscL, we calculated how two such proteins embedded in a bilayer, able to otherwise freely diffuse, will communicate their conformational state via the bilayer, leading to cooperative channel gating. Additionally, the interactions are often attractive, and hence lead to spatial dimerization that is heavily dependent on the proteins' conformations.
Figure 2. Deformations in the bilayer surrounding two transmembrane proteins lead to elastic interactions, capable of communicating information about conformational state and spatially organizing the proteins. a) The interaction between two closed MscL channels. b) The interaction between an open and a closed MscL channel. c) The interaction between two open MscL channels.
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