Phillips.indd NS .indd

it has provided particularly useful insights is the analysis of the function of membrane proteins, specifically with respect to their interactions with the surrounding lipid molecules. Models and experiments show that rather than being a passive bystander in the function of membrane-bound proteins, the membrane can at times have an essential role in determining the function of these proteins. Cell membranes are the barriers that separate the cytoplasm of the cell from the external world and internally compartmentalize eukaryotic cells into organelles. Far from being inert, biological membranes are key components in sensory and signalling pathways. They are highly controlled barriers that allow the directed flux of molecules into and out of the cytoplasm, and they have an analogous role in intracellular trafficking and energy production in cellular organelles. At the microscopic scale, biological membranes are a crowded mix of membrane proteins and their lipid partners. Our understanding of this complicated environment is constantly being refined by new experiments. The data that emerge often reveal functional and quantitative relations between biologically interesting parameters (for example, the open probability for ion channels as a function of driving forces such as voltage or membrane tension), and carry with them an imperative for models of the underlying phenomena. Each generation of new experiments refines the models used to describe membranes, a topic elegantly reviewed elsewhere. One case study that illustrates this interplay between quantitative models and experiments concerns the analysis of the structure and function of mechanosensitive channels, reconstituted in simple lipid bilayers. The data demonstrate that the physicochemical properties of the surrounding lipid bilayer result in predictable and stereotyped consequences for channel function in artificial lipid membranes, although the interactions between lipids and membrane proteins have broader significance. The concepts we present in this Review are predicted to have functional and structural significance for any protein whose function requires the remodelling of the protein– membrane interface. These models are used first to examine the properties of an isolated channel, followed by examples of an added layer of complexity resulting from membrane-mediated interactions between the channels. Mechanosensitive channels and biological membranes The idea that sequence dictates structure, which in turn dictates function, is a second central dogma of biology. A powerful example of this dictum is in the context of membrane proteins. The stunning structures obtained of membrane machines, from the light-gathering apparatus of photosynthesis to the voltage-gated channels that allow neurons to propagate electrical impulses and the bacterial sensors that detect osmotic stress, provide key insights into the mechanisms by which these proteins respond to stimuli such as light, voltage and membrane tension. In many cases, complementary functional studies show us that the lipid bilayer is not a passive bystander in membrane protein function, as shown systematically elsewhere. In this context, the word ‘structure’ usually refers to atomic positions, but a more coarse-grained picture of structure, captured by ideas from continuum elasticity, can reproduce many important membrane properties. In these models, ‘structure’ refers to quantities such as the local thickness and curvature of the lipid bilayer surrounding the membrane protein of interest. This is in contrast to molecular dynamics, which explicitly represents the position of every atom of both the protein and the lipid bilayer. As a concrete example, we will consider bacterial mechanosensitive channels. The structure, function and physiology of mechanosensitive channels have been studied extensively. As shown in Fig. 1, bacterial mechanosensitive channels are gated by membrane tension. More precisely, a pipette is used to grab a patch of membrane containing these channels and the current passing through the protein-encumbered membrane is measured as a function of the pipette suction pressure or membrane tension. These experiments demonstrate a relation between the open probability of the channel and the pipette pressure that is dependent on the properties of the lipid membrane in which the proteins find themselves (such as the tail lengths of the lipids, which can result in a mismatch between the protein and the bilayer thickness). Analysis of the gating free energy reveals that the quantitative dependence of the gating tension on the length of the lipid acyl tail matches the prediction from elastic bilayer models. Studies of mechanosensitive channels therefore reveal not only the importance of the lipid environment but show that, at least in the case of hydrophobic mismatch, where the hydrophobic core of the bilayer has a different thickness from the hydrophobic region of a transmembrane protein, the mechanism can be understood in terms of a coarse-grained elastic model of the bilayer. Emerging roles for lipids in shaping membrane-protein function