A necessary step in the origin of life was the generation of a discrete barrier, a boundary layer, that serves to separate the living non-equilibrium reaction system from the rest of the universe. This boundary layer, the structural ancestor of the plasma membrane of modern cells, serves to maintain the integrity of the living system and mediates the movement of materials and energy into and out of the cell. Based on our current observations, the plasma membrane of all modern cells appears to be a homologous structure derived from a precursor present in the last common ancestor of life. So what is the structure of this barrier (plasma) membrane? How is it built and how does it work?
When a new cell is formed its plasma membrane is derived from the plasma membrane of the progenitor cell. As the cell grows, new molecules must be added into the membrane to enable it to increase its surface area. Biological membranes are composed of two general classes of molecules, proteins (which we will discuss in much greater detail in the next section of the course) and lipids. It is worth noting explicitly here that, unlike a number of other types of molecules we will be considering, such as proteins, nucleic acids, and carbohydrates, lipids are not a structurally coherent group, that is they do not have one particular basic structure. Structurally diverse molecules, such as cholesterol and phospholipids, are both considered lipids. While there is a relatively small set of common lipid types, there are many different lipids found in biological systems and the characterization of their structure and function(s) has led to a new area of specialization known as lipidomics165.
All lipids have two distinct domains: a hydrophilic (circled in red in this figure domain characterized by polar regions and one or more hydrophobic/hydroapathetic domains that are usually made up of C and H and are non-polar. Lipids are amphipathic. In aqueous solution, entropic effects will drive the hydrophobic/hydroapathetic parts of the lipid out of aqueous solution. But in contrast to totally non-polar molecules, like oils, the hydrophobic/hydroapathetic part of the lipid is connected to a hydrophilic domain that is soluble in water. Lipid molecules deal with this dichotomy by associating with other lipid molecules in multimolecular structures in which the interactions between the hydrophilic parts of the lipid molecule and water molecules are maximized and the interactions between the lipid’s hydrophobic/hydroapathetic parts and water are minimized. Many different multi-molecular structures can be generated that fulfill these constraints. The structures that form depend upon the details of the system, including the shapes of the lipid molecules and the relative amounts of water and lipid present, but the reason these structures self- assemble is because their formation leads to an increase in the overall entropy of the system, a somewhat counterintuitive idea. For example, in a micelle the hydrophilic region is in contact with the water, while the hydrophobic regions are inside, away from direct contact with water. This leads to a more complete removal of the hydrophobic domain of the lipid from contact with water than can be arrived at by a purely hydrophobic oil molecule, so unlike oil, lipids can form stable structures in solution. The diameter and shape of the micelle is determined by the size of its hydrophobic domain. As this domain gets longer, the center of the micelle becomes more crowded. Another type of organization that avoids “lipid-tail crowding” is known as a bilayer vesicle. Here there are two layers of lipid molecules, pointing in opposite directions. The inner layer surrounds a water-filled region, the lumen of the vesicle, while the outer layer interacts with the external environment. In contrast to the situation within a micelle, the geometry of a vesicle means that there is significantly less crowding as a function of lipid tail length. Crowding is further reduced as a vesicle increases in size to become a cellular membrane. Micelles and vesicles can form a colloid-like system with water, that is they exist as distinct structures that can remain suspended in a stable state. We can think of the third type of structure, the planar membrane, as simply an expansion of the vesicle to a larger and more irregular size. Now the inner layer faces the inner region of the cell (which is mostly water) and the opposite region faces the outside world. For the cell to grow, new lipids have to be inserted into both inner and outer layers of the membrane; how exactly this occurs typically involves interactions with proteins. For example, there are proteins that can move a lipid from the inner to the outer domain of a membrane (they flip the lipid between layers, and are known as flipases); while but the details are beyond our scope here you might be able to generate a plausible mechanism. A number of distinct mechanisms are used to insert molecules into membranes, but they all involve a pre-existing membrane – this is another aspect of the continuity of life. Totally new cellular membranes do not form, membranes are built on pre-existing membranes. For example, a vesicle (that is a spherical lipid bilayer) could fuse into or emerge from a planar membrane. These processes are typically driven by thermodynamically favorable reactions involving protein-based molecular machines. When the membrane involved is the plasma (boundary) membrane, these processes are known as exocytosis and endocytosis, respectively. These terms refer explicitly to the fate of the material within the vesicle. Exocytosis releases that material from the vesicle interior into the outside world, whereas endocytosis captures material from outside of the cell and brings it into the cell. Within a cell, vesicles can fuse and emerge from one another.
As noted above, there are hundreds of different types of lipids, generated by a variety of biosynthetic pathways catalyzed by proteins encoded in the genetic material. We will not worry too much about all of these different types of lipids, but we will consider two generic classes, the glycerol-based lipids and cholesterol, because considerations of their structures illustrates general ideas related to membrane behavior. In bacteria and eukaryotes, glycerol-based lipids are typically formed from the highly hydrophilic molecule glycerol combined with two or three fatty acid molecules. Fatty acids contain a long chain hydrocarbon with a polar (carboxylic acid) head group. The nature of these fatty acids influences the behavior of the membrane formed. Often these fatty acids have what are known as saturated hydrocarbon tails. A saturated hydrocarbon contains only single bonds between the carbon atoms of its tail domain. While these chains can bend and flex, they tend to adopt a more or less straight configuration. In this straight configuration, they pack closely with one another, which maximizes the lateral (side to side) van der Waals interactions between them. Because of the extended surface contact between the chains, lipids with saturated hydrocarbon chains are typically solid around room temperature. On the other hand, there are cases where the hydrocarbon tails are “unsaturated”, that is they contain double bonds (–C=C–) in them. These are typically more fluid and flexible. This is because unsaturated hydrocarbon chains have permanent kinks in them (because of the rigid nature and geometry of the C=C bonds), so they cannot pack as regularly as saturated hydrocarbon chains. The less regular packing means that there is less interaction area between the molecules, which lowers the strength of the van der Waals interactions between them. This in turn, lowers the temperature at which these bilayers change from a solid (no movement of the lipids relative to each other within the plane of the membrane) to a liquid (much freer movements). Recall that the strength of interactions between molecules determines how much energy is needed to overcome a particular type of interaction. Because these van der Waals intermolecular interactions are relatively weak, changes in environmental temperature influence the physical state of the membrane. The liquid-like state is often referred to as the fluid state. The importance of membrane state is that it can influence the behavior and activity of membrane proteins. If the membrane is in a solid state, proteins embedded within the membrane will be immobile; if is in the liquid state, these proteins will move by diffusion, that is, by thermally driven movement, within the plane of the membrane. In addition, since lipids and proteins are closely associated with one another in the membrane, the physical state of the membrane can influence the activity of embedded proteins, a topic to which we will return.
Cells can manipulate the solid-to-liquid transition temperature of their membrane by altering the membrane’s lipid composition. For example, by altering the ratio of saturated to unsaturated chains present. This level of control involves altering the activities of the enzymes involved in saturation/desaturation reactions. That these enzymes can be regulated implies a feedback mechanism, by whicheither temperature or membrane fluidity acts to regulate metabolic processes. This type of feed back mechanism is part of what is known as the homeostatic and adaptive system of the cell (and the organism) and is another topic we will return to toward the end of the course.
There are a number of differences between the lipids used in bacterial and eukaryotic organisms and archaea166. For example, instead of hydrocarbon chains, archaeal lipids are constructed of isoprene (CH2=C(CH3)CH=CH2) polymers linked to the glycerol group through an ether (rather than an ester) linkage. The bumpy and irregular shape of the isoprene groups (compared to the relatively smooth saturated hydrocarbon chains) means that archaeal membranes will tend to melt (go from solid to liquid) at lower temperatures167. At the same time the ether linkage is more stable (requires more energy to break) than the ester linkage. It remains unclear why it is that while all organisms use glycerol-based lipids, the bacteria and the eukaryotes use hydrocarbon chain lipids, while the archaea use isoprene-based lipids. One speculation is that the archaea were originally adapted to live at higher temperatures, where the greater stability of the ether linkage would provide a critical advantage.
At the highest temperatures, thermal motion might be expected to disrupt the integrity of the membrane, allowing small charged molecules (ions) and hydrophilic molecules through168. Given the importance of membrane integrity, you will (perhaps) not be surprised to find “double-headed” lipids in organisms that live at high temperatures, known as thermophiles and hyperthermophiles. These lipid molecules have a two distinct hydrophilic glycerol moieties, one located at each end of the molecule; this enables them to span the membrane. The presumption is that such lipids act to stabilize the membrane against the disruptive effects of high temperatures - important since some archaea live (happily, apparently) at temperatures up to 110 ºC169. Similar double-headed lipids are also found in bacteria that live in high temperature environments.
That said, the solid-fluid nature of biological membranes, as a function of temperature, is complicated by the presence of cholesterol and structurally similar lipids. For example, in eukaryotes the plasma membrane can contain as much as 50% (by number of lipid molecules present) cholesterol. Cholesterol has a short bulky hydrophobic domain that does not pack well with other lipids a hydrocarbon chain lipid (left) and cholesterol (right)). When present, it dramatically influences the solid-liquid behavior of the membrane. The diverse roles of lipids is a complex subject that goes beyond our scope here170.
166 A re-evaluation of the archaeal membrane lipid biosynthetic pathway: http://www.nature.com/nrmicro/journa...micro3260.html
167 The origin and evolution of Archaea: a state of the art: http://rstb.royalsocietypublishing.o...1470/1007.full
168 Ion permeability of the cytoplasmic membrane limits the maximum growth temperature of bacteria and archaea. http://www.ncbi.nlm.nih.gov/pubmed/8825096
169 You might want to consider how this is possible and under want physical conditions you might find these “thermophilic” archaea.
170 At this point, such a search recovers 636 papers (and there are many more than concern lipid function but do not contain lipidomics in the title.