11.1Biological Membranes

Membrane structures are essential for cells. They include the cell membrane that separates the cell from the external environment and various membranous structures found within eukaryotic cells. Biological membranes are basically composed of a lipid bilayer (6–10 nm thick; Fig. 11-2), and the primary components of the lipids constituting this bilayer are phospholipids and cholesterol (see Chapter 6).
The properties of phospholipids that constitute the lipid bilayer change discontinuously with temperature. This type of variation is called phase transition, and this phenomenon is same as that observed when water changes to ice or water vapor. When the temperature is low, the lipid bilayer enters the crystalline phase, and when the temperature increases, it transitions through a gel phase to a liquid crystalline phase (Fig. 11-3A). In the crystalline phase, when the hydrocarbon chains of the phospholipids are stretched out, the chains are bound to each other by Van der Waals interactions, making it difficult for the phospholipids to move. On the other hand, in the liquid crystalline phase, when the hydrocarbon chains are bent and their mutual bonds are weak, the phospholipids actively move by molecular motion. Examples of this include rotation, lateral and transverse diffusion (flip-flop from one side of the bilayer to the other) of phospholipids, and flexion motion of the fatty acid moiety (Fig. 11-3B). Such active movement of phospholipids increases with increase in temperature, and this provides the fluidity required to perform the various functions of biological membranes. In addition, the inner and outer layers of the lipid bilayer that constitute biological membranes have different proportions of lipid components. These differences are regulated by flip-flop of lipids.
Many different types of transmembrane proteins and extrinsic membrane proteins are associated with the lipid bilayer of biological membranes (Fig. 11-4). Transmembrane proteins are embedded in the biological membrane by α-helix and β-sheet structures comprising hydrophobic amino acids. Many of these transmembrane proteins play a role in forming passages through which substances can pass across the biological membrane and in transducing information from the outside to the inside of the cell. Moreover, in extrinsic membrane proteins, the hydrophobic segments are embedded in the biological membrane, the fatty acid bound to the protein is incorporated into the biological membrane, or the protein selectively binds to a specific phospholipid in order to bind to the surface of the biological membrane. These proteins are involved in numerous different functions performed at or near the biological membrane.

Fig. 11-2 Biological membranes

An electron microscope photograph showing a biological membrane, and a molecular model of the phospholipid bilayer that forms the biological membrane. Refer to Chapter 6 for futher details on the phospholipid circled with the dotted line.

The lipid bilayer, which is the basic structure of biological membranes, forms a hydrophobic barrier, and therefore, the free passage of substances is restricted with an exception for some molecules. For example, small hydrophobic molecules (such as gases) or small uncharged molecules can freely permeate the biological membrane. However, small charged molecules (e.g., different types of ions), large uncharged polar molecules, and charged polar molecules cannot permeate the biological membrane by diffusion (Fig. 11-5A). Cells need to intake various substances (such as nutrients and ions) from the external environment and expel intracellular substances for survival. They also need information from the outside to be effectively transduced into the cell. Thus, biological membranes have developed various mechanisms (see Chapter 14) related to substance transport (Fig. 11-5B, C) and signal transduction.
Moreover, the inner side of the cell membrane contains a structure called the plasmalemmal undercoat (Fig. 11-6), which structurally reinforces the thin membrane and fastens the membrane proteins that tend to move freely to a specific region.

Fig. 11-3 Properties of the lipid bilayer

(A) A molecular model showing changes in the properties of the lipid bilayer caused by temperature. As the temperature increases, the bilayer passes from a crystalline phase through a gel phase to a liquid crystalline phase. (B) The constituent molecules of the lipid bilayer in the liquid crystalline phase move vigorously. For ease of understanding, the crystalline phase structure is used to show the schematics. Within these movements, inverted movement requires a lot of energy, and thus, occurrence of this movement only with molecular movements is rare.

Fig. 11-4 Types of membrane-bound proteins

Biological membranes contain transmembrane proteins found penetrating the membrane (such as channels for substances to pass through or signalling molecules) and membrane surface proteins that bind to the membrane (such as enzymes or signalling molecules).

Fig. 11-5 Permeability of the cell membrane

(A) Only some molecules can pass through the cell membrane by diffusion. (B) Membrane proteins called channels, carriers (or transporters), and pumps are involved in transporting substances across the cell membrane. To transport proteins across the membrane, carriers use changes in the steric structure of the proteins caused by binding to them. Pumps use energy from ATP hydrolysis to transport ions and substances against the concentration gradient. (C) Transported substances can also be classified by direction.

Fig. 11-6 Structure of the cell membrane lining

Directly below the cell membrane, there is an undercoating structure primarily comprising the cytoskeleton, which gives stability to the membrane structure. Many of the proteins in the cell membrane are found in a certain distribution pattern attached to this distribution pattern.


The History of Understanding the Molecular Structure of Ion Channels

Friedrich Ostwald, who won the Nobel Prize for Chemistry for his discovery in 1909, revealed that electrical signals in living tissues were generated by the passage of ions across the cell membrane. By the 1920s, scientists were advocating the concept of ion channels found in the cell membrane. Alan Hodgkin and Andrew Huxley won the Nobel Prize for Physiology or Medicine in 1963 for proving that generation of an action potential by nerve cells could be represented as an equation of permeability by Na+ and K+. By the 1970s, a filter structure was proposed to be present in ion channels that selectively allowed passage of only specific ions. This indicates that the K+ channel allows the passage of K+ but not Na+, irrespective of the fact that K+ (2.7 Å) has a larger atomic size than Na+ (1.9 Å). Bertil Hille described this phenomenon as theoretically based on intermolecular bonds (the filter theory). Unfortunately, this theory could not be proved until the molecular structure of the ion channels was understood by structural analysis.
Later, as a result of technological progress such as purification and isolation of proteins and their structural analysis by X-ray crystallography, analysis of the molecular structure of the ion channels became possible. This is how Roderick MacKinnon discovered the molecular structure of the K+ channel by structurally analyzing it in bacteria, going on to win the Nobel Prize for Chemistry in 2003.
In the structure of the K+ channel discovered by MacKinnon, four proteins assemble to form a passageway (with a diameter of approximately 3 Å) that allows the movement of K+ (Column Fig. 11-1). When K+ passes through this channel, the water molecules attracted to the ions are removed, and an ionic reaction must proceed with the oxygen atoms of the carbonyl groups (-CO-) of the amino acids present in the passageway. The type of reaction that occurs at this time is different for K+ and Na+, which have different sizes. The small-sized Na+ ions are unable to react smoothly with all oxygen atoms of the four carbonyl groups distributed facing the passageway; therefore, all water molecules are stripped off, and it is no longer possible for Na+ to pass through the passageway of the channel. This difference is believed to form the filter mechanism wherein Na+ is unable to pass through even if K+ does. This fact also proves that Hille’s hypothesis of a filter theory was correct.

Column Fig. 11-1 K+ channel in bacteria

(A) The K+ channel is composed of tetrameric transmembrane proteins through the center of which is a passageway for ions. Ions in water attach to the water molecule to become hydrated, and in that state, the overall molecular size is so large that they cannot pass through the passageway. (B) Na+ is smaller in size than K+ and thus cannot easily react with the carbonyl groups of the amino acids constituting the filter unit.

Top of Page